Skip to main content

Advertisement

SpringerLink
Log in

Gaucher disease – more than just a rare lipid storage disease

  • Review
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Gaucher disease (GD), one of the most common lysosomal storage diseases, is caused by mutations in the gene, GBA1, that leads to defective glucocerebrosidase activity resulting in the accumulation and storage of glycosphingolipids. However, the pathophysiology of GD is more complicated leading to various associated conditions such as skeletal manifestations and Parkinson’s disease (PD). These may result from oxidative stress and inflammatory responses due to complex interconnection of downstream factors such as substrate accumulation, endoplasmic reticulum (ER) stress, unfolded protein response (UPR), calcium dysregulation, mitochondrial dysfunction, defective autophagy, accumulation of α-synuclein aggregates, altered secretion and function of extracellular vesicles (EVs), and immunologic hyperactivity. Here we provide an overview of lysosomal storage diseases followed by a comprehensive review of the factors contributing to oxidative stress and inflammation in GD pathophysiology, mechanisms underlying the possible associated complications, current established treatments for GD, their limitations, and potential primary and adjunctive treatment options targeting these factors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

We’re sorry, something doesn't seem to be working properly.

Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

Fig. 1

Similar content being viewed by others

Data availability

Not applicable.

Notes

  1. Mutation nomenclature is complicated, as the numbering of the mutated amino acid was changed several years ago to include the 39-amino-acid leader sequence (newer numbering shown in parentheses).

References

  1. Lim CY, Zoncu R (2016) The lysosome as a command-and-control center for cellular metabolism. J Cell Biol 214:653–664. https://doi.org/10.1083/jcb.201607005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Schwake M, Schröder B, Saftig P (2013) Lysosomal membrane proteins and their central role in physiology. Traffic 14:739–748. https://doi.org/10.1111/tra.12056

    Article  CAS  PubMed  Google Scholar 

  3. Weinreb NJ, Brady RO, Tappel AL (1968) The lysosomal localization of sphingolipid hydrolases. Biochim Biophys Acta 159:141–146. https://doi.org/10.1016/0005-2744(68)90251-9

    Article  CAS  PubMed  Google Scholar 

  4. Grabowski GA, Antommaria AHM, Kolodny EH, Mistry PK (2021) Gaucher disease: basic and translational science needs for more complete therapy and management. Mol Genet Metab 132: 59-75. https://doi.org/10.1016/j.ymgme.2020.12.291

  5. Andrade-Campos MM, de Frutos LL, Cebolla JJ, Serrano-Gonzalo I, Medrano-Engay B, Roca-Espiau M, Gomez-Barrera B, Pérez-Heredia J, Iniguez D, Giraldo P (2020) Identification of risk features for complication in Gaucher’s disease patients: a machine learning analysis of the Spanish registry of Gaucher disease. Orphanet J Rare Dis 15:256. https://doi.org/10.1186/s13023-020-01520-7

    Article  PubMed  PubMed Central  Google Scholar 

  6. Burrow TA, Sun Y, Prada CE, Bailey L, Zhang W, Brewer A, Wu SW, Setchell KDR, Witte D, Cohen MB et al (2015) CNS, lung, and lymph node involvement in Gaucher disease type 3 after 11 years of therapy: clinical, histopathologic, and biochemical findings. Mol Genet Metab 114:233–241. https://doi.org/10.1016/j.ymgme.2014.08.011

    Article  CAS  PubMed  Google Scholar 

  7. Revel-Vilk S, Fuller M, Zimran A (2020) Value of glucosylsphingosine (Lyso-Gb1) as a biomarker in Gaucher disease: a systematic literature review. Int J Mol Sci 21. https://doi.org/10.3390/ijms21197159

  8. Bendikov-Bar I, Horowitz M (2012) Gaucher disease paradigm: from ERAD to comorbidity. Hum Mutat 33:1398–1407. https://doi.org/10.1002/humu.22124

    Article  CAS  PubMed  Google Scholar 

  9. Wong K, Sidransky E, Verma A, Mixon T, Sandberg GD, Wakefield LK, Morrison A, Lwin A, Colegial C, Allman JM et al (2004) Neuropathology provides clues to the pathophysiology of Gaucher disease. Mol Genet Metab 82:192–207. https://doi.org/10.1016/j.ymgme.2004.04.011

    Article  CAS  PubMed  Google Scholar 

  10. Bennett LL, Mohan D (2013) Gaucher disease and its treatment options. Ann Pharmacother 47:1182–1193. https://doi.org/10.1177/1060028013500469

    Article  PubMed  Google Scholar 

  11. Stirnemann J, Belmatoug N, Camou F, Serratrice C, Froissart R, Caillaud C, Levade T, Astudillo L, Serratrice J, Brassier A et al (2017) A review of Gaucher disease pathophysiology, clinical presentation and treatments. Int J Mol Sci 18. https://doi.org/10.3390/ijms18020441

  12. Charrow J, Andersson HC, Kaplan P, Kolodny EH, Mistry P, Pastores G, Rosenbloom BE, Scott CR, Wappner RS, Weinreb NJ et al (2000) The Gaucher registry: demographics and disease characteristics of 1698 patients with Gaucher disease. Arch Intern Med 160:2835–2843. https://doi.org/10.1001/archinte.160.18.2835

    Article  CAS  PubMed  Google Scholar 

  13. Elstein D, Alcalay R, Zimran A (2015) The emergence of Parkinson disease among patients with Gaucher disease. Best Pract Res Clin Endocrinol Metab 29:249–259. https://doi.org/10.1016/j.beem.2014.08.007

    Article  PubMed  Google Scholar 

  14. Biegstraaten M, Mengel E, Maródi L, Petakov M, Niederau C, Giraldo P, Hughes D, Mrsic M, Mehta A, Hollak CE et al (2010) Peripheral neuropathy in adult type 1 Gaucher disease: a 2-year prospective observational study. Brain 133:2909–2919. https://doi.org/10.1093/brain/awq198

    Article  PubMed  Google Scholar 

  15. McNeill A, Roberti G, Lascaratos G, Hughes D, Mehta A, Garway-Heath DF, Schapira AH (2013) Retinal thinning in Gaucher disease patients and carriers: results of a pilot study. Mol Genet Metab 109:221–223. https://doi.org/10.1016/j.ymgme.2013.04.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ida H, Rennert OM, Iwasawa K, Kobayashi M, Eto Y (1999) Clinical and genetic studies of Japanese homozygotes for the Gaucher disease L444P mutation. Hum Genet 105:120–126. https://doi.org/10.1007/s004399900076

    Article  CAS  PubMed  Google Scholar 

  17. Andrew BT, Sonya B, Gregory G (2011) Prevalence and management of Gaucher disease. Pediatric Health, Medicine and Therapeutics 2011:59–73. https://doi.org/10.2147/PHMT.S12499

    Article  Google Scholar 

  18. Nagral A (2014) Gaucher disease J Clin Exp Hepatol 4:37–50. https://doi.org/10.1016/j.jceh.2014.02.005

    Article  PubMed  Google Scholar 

  19. Zampieri S, Cattarossi S, Bembi B, Dardis A (2017) GBA analysis in next-generation era: pitfalls, challenges, and possible solutions. J Mol Diagn 19:733–741. https://doi.org/10.1016/j.jmoldx.2017.05.005

    Article  CAS  PubMed  Google Scholar 

  20. Grabowski GA (2008) Phenotype, diagnosis, and treatment of Gaucher’s disease. Lancet 372:1263–1271. https://doi.org/10.1016/S0140-6736(08)61522-6

    Article  CAS  PubMed  Google Scholar 

  21. Alaei M, Jafari N, Rohani F, Ahmadabadi F, Azadi R (2018) Are there neurological symptoms in type 1 of Gaucher disease? Iran J Child Neurol 12:99–106

    PubMed  PubMed Central  Google Scholar 

  22. Ługowska A, Hetmańczyk-Sawicka K, Iwanicka-Nowicka R, Fogtman A, Cieśla J, Purzycka-Olewiecka JK, Sitarska D, Płoski R, Filocamo M, Lualdi S et al (2019) Gene expression profile in patients with Gaucher disease indicates activation of inflammatory processes. Sci Rep 9:6060. https://doi.org/10.1038/s41598-019-42584-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Bultron G, Kacena K, Pearson D, Boxer M, Yang R, Sathe S, Pastores G, Mistry PK (2010) The risk of Parkinson’s disease in type 1 Gaucher disease. J Inherit Metab Dis 33:167–173. https://doi.org/10.1007/s10545-010-9055-0

    Article  PubMed  PubMed Central  Google Scholar 

  24. Gan-Or Z, Giladi N, Orr-Urtreger A (2009) Differential phenotype in Parkinson’s disease patients with severe versus mild GBA mutations. Brain 132:e125. https://doi.org/10.1093/brain/awp161

    Article  CAS  PubMed  Google Scholar 

  25. Nichols WC, Pankratz N, Marek DK, Pauciulo MW, Elsaesser VE, Halter CA, Rudolph A, Wojcieszek J, Pfeiffer RF, Foroud T et al (2009) Mutations in GBA are associated with familial Parkinson disease susceptibility and age at onset. Neurology 72:310–316. https://doi.org/10.1212/01.wnl.0000327823.81237.d1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Alcalay RN, Dinur T, Quinn T, Sakanaka K, Levy O, Waters C, Fahn S, Dorovski T, Chung WK, Pauciulo M et al (2014) Comparison of Parkinson risk in Ashkenazi Jewish patients with Gaucher disease and GBA heterozygotes. JAMA Neurol 71:752–757. https://doi.org/10.1001/jamaneurol.2014.313

    Article  PubMed  PubMed Central  Google Scholar 

  27. Chérin P, Rose C, de Roux-Serratrice C, Tardy D, Dobbelaere D, Grosbois B, Hachulla E, Jaussaud R, Javier RM, Noël E et al (2010) The neurological manifestations of Gaucher disease type 1: the French Observatoire on Gaucher disease (FROG). J Inherit Metab Dis 33:331–338. https://doi.org/10.1007/s10545-010-9095-5

    Article  PubMed  Google Scholar 

  28. Kartha RV, Joers J, Terluk MR, Travis A, Rudser K, Tuite PJ, Weinreb NJ, Jarnes JR, Cloyd JC, Öz G (2020) Neurochemical abnormalities in patients with type 1 Gaucher disease on standard of care therapy. J Inherit Metab Dis 43:564–573. https://doi.org/10.1002/jimd.12182

    Article  CAS  PubMed  Google Scholar 

  29. Schiavone S, Jaquet V, Trabace L, Krause KH (2013) Severe life stress and oxidative stress in the brain: from animal models to human pathology. Antioxid Redox Signal 18:1475–1490. https://doi.org/10.1089/ars.2012.4720

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Vogt Weisenhorn DM, Giesert F, Wurst W (2016) Diversity matters - heterogeneity of dopaminergic neurons in the ventral mesencephalon and its relation to Parkinson’s Disease. J Neurochem 139(Suppl 1):8–26. https://doi.org/10.1111/jnc.13670

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Dueck H, Eberwine J, Kim J (2016) Variation is function: are single cell differences functionally important?: testing the hypothesis that single cell variation is required for aggregate function. BioEssays 38:172–180. https://doi.org/10.1002/bies.201500124

    Article  PubMed  Google Scholar 

  32. Kaufman RJ (1999) Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev 13:1211–1233. https://doi.org/10.1101/gad.13.10.1211

    Article  CAS  PubMed  Google Scholar 

  33. Reczek D, Schwake M, Schröder J, Hughes H, Blanz J, Jin X, Brondyk W, Van Patten S, Edmunds T, Saftig P (2007) LIMP-2 is a receptor for lysosomal mannose-6-phosphate-independent targeting of beta-glucocerebrosidase. Cell 131:770–783. https://doi.org/10.1016/j.cell.2007.10.018

    Article  CAS  PubMed  Google Scholar 

  34. Ron D, Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8:519–529. https://doi.org/10.1038/nrm2199

    Article  CAS  PubMed  Google Scholar 

  35. Schröder M, Kaufman RJ (2005) The mammalian unfolded protein response. Annu Rev Biochem 74:739–789. https://doi.org/10.1146/annurev.biochem.73.011303.074134

    Article  CAS  PubMed  Google Scholar 

  36. Jian Z, Li JB, Ma RY, Chen L, Wang XF, Xiao YB (2012) Pivotal role of activating transcription factor 6α in myocardial adaptation to chronic hypoxia. Int J Biochem Cell Biol 44:972–979. https://doi.org/10.1016/j.biocel.2012.03.004

    Article  CAS  PubMed  Google Scholar 

  37. Zhang K, Kaufman RJ (2008) From endoplasmic-reticulum stress to the inflammatory response. Nature 454:455–462. https://doi.org/10.1038/nature07203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lee YJ, Kim SJ, Heo TH (2011) Protective effect of catechin in type I Gaucher disease cells by reducing endoplasmic reticulum stress. Biochem Biophys Res Commun 413:254–258. https://doi.org/10.1016/j.bbrc.2011.08.080

    Article  CAS  PubMed  Google Scholar 

  39. Braunstein H, Maor G, Chicco G, Filocamo M, Zimran A, Horowitz M (2018) UPR activation and CHOP mediated induction of GBA1 transcription in Gaucher disease. Blood Cells Mol Dis 68:21–29. https://doi.org/10.1016/j.bcmd.2016.10.025

    Article  CAS  PubMed  Google Scholar 

  40. Maor G, Rencus-Lazar S, Filocamo M, Steller H, Segal D, Horowitz M (2013) Unfolded protein response in Gaucher disease: from human to Drosophila. Orphanet J Rare Dis 8:140. https://doi.org/10.1186/1750-1172-8-140

    Article  PubMed  PubMed Central  Google Scholar 

  41. Suzuki T, Shimoda M, Ito K, Hanai S, Aizawa H, Kato T, Kawasaki K, Yamaguchi T, Ryoo HD, Goto-Inoue N et al (2013) Expression of human Gaucher disease gene GBA generates neurodevelopmental defects and ER stress in Drosophila eye. PLoS ONE 8:e69147. https://doi.org/10.1371/journal.pone.0069147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Li M, Liu Y, Xia F, Wu Z, Deng L, Jiang R, Guo FJ (2014) Progranulin is required for proper ER stress response and inhibits ER stress-mediated apoptosis through TNFR2. Cell Signal 26:1539–1548. https://doi.org/10.1016/j.cellsig.2014.03.026

    Article  CAS  PubMed  Google Scholar 

  43. Jian J, Zhao S, Tian QY, Liu H, Zhao Y, Chen WC, Grunig G, Torres PA, Wang BC, Zeng B et al (2016) Association between progranulin and Gaucher disease. EBioMedicine 11:127–137. https://doi.org/10.1016/j.ebiom.2016.08.004

    Article  PubMed  PubMed Central  Google Scholar 

  44. Jian J, Tian QY, Hettinghouse A, Zhao S, Liu H, Wei J, Grunig G, Zhang W, Setchell KDR, Sun Y et al (2016) Progranulin recruits HSP70 to β-glucocerebrosidase and is therapeutic against Gaucher disease. EBioMedicine 13:212–224. https://doi.org/10.1016/j.ebiom.2016.10.010

    Article  PubMed  PubMed Central  Google Scholar 

  45. Horowitz M, Elstein D, Zimran A, Goker-Alpan O (2016) New directions in Gaucher disease. Hum Mutat 37:1121–1136. https://doi.org/10.1002/humu.23056

    Article  CAS  PubMed  Google Scholar 

  46. Maor G, Cabasso O, Krivoruk O, Rodriguez J, Steller H, Segal D, Horowitz M (2016) The contribution of mutant GBA to the development of Parkinson disease in Drosophila. Hum Mol Genet 25:2712–2727. https://doi.org/10.1093/hmg/ddw129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Chong WC, Shastri MD, Eri R (2017) Endoplasmic reticulum stress and oxidative stress: a vicious nexus implicated in bowel disease pathophysiology. Int J Mol Sci 18. https://doi.org/10.3390/ijms18040771

  48. Oka OB, Bulleid NJ (2013) Forming disulfides in the endoplasmic reticulum. Biochim Biophys Acta 1833:2425–2429. https://doi.org/10.1016/j.bbamcr.2013.02.007

    Article  CAS  PubMed  Google Scholar 

  49. Delaunay-Moisan A, Appenzeller-Herzog C (2015) The antioxidant machinery of the endoplasmic reticulum: protection and signaling. Free Radic Biol Med 83:341–351. https://doi.org/10.1016/j.freeradbiomed.2015.02.019

    Article  CAS  PubMed  Google Scholar 

  50. Rossi R, Dalle-Donne I, Milzani A, Giustarini D (2006) Oxidized forms of glutathione in peripheral blood as biomarkers of oxidative stress. Clin Chem 52:1406–1414. https://doi.org/10.1373/clinchem.2006.067793

    Article  CAS  PubMed  Google Scholar 

  51. Schmitt B, Vicenzi M, Garrel C, Denis FM (2015) Effects of N-acetylcysteine, oral glutathione (GSH) and a novel sublingual form of GSH on oxidative stress markers: a comparative crossover study. Redox Biol 6:198–205. https://doi.org/10.1016/j.redox.2015.07.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kartha RV, Terluk MR, Brown R, Travis A, Mishra UR, Rudser K, Lau H, Jarnes JR, Cloyd JC, Weinreb NJ (2020) Patients with Gaucher disease display systemic oxidative stress dependent on therapy status. Mol Genet Metab Rep 25:100667. https://doi.org/10.1016/j.ymgmr.2020.100667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Gegg ME, Schapira AH (2016) Mitochondrial dysfunction associated with glucocerebrosidase deficiency. Neurobiol Dis 90:43–50. https://doi.org/10.1016/j.nbd.2015.09.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kim S, Wong YC, Gao F, Krainc D (2021) Dysregulation of mitochondria-lysosome contacts by GBA1 dysfunction in dopaminergic neuronal models of Parkinson’s disease. Nat Commun 12:1807. https://doi.org/10.1038/s41467-021-22113-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. King C, Sengupta P, Seo AY, Lippincott-Schwartz J (2020) ER membranes exhibit phase behavior at sites of organelle contact. Proc Natl Acad Sci U S A 117:7225–7235. https://doi.org/10.1073/pnas.1910854117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Höglinger D, Burgoyne T, Sanchez-Heras E, Hartwig P, Colaco A, Newton J, Futter CE, Spiegel S, Platt FM, Eden ER (2019) NPC1 regulates ER contacts with endocytic organelles to mediate cholesterol egress. Nat Commun 10:4276. https://doi.org/10.1038/s41467-019-12152-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Cleeter MW, Chau KY, Gluck C, Mehta A, Hughes DA, Duchen M, Wood NW, Hardy J, Mark Cooper J, Schapira AH (2013) Glucocerebrosidase inhibition causes mitochondrial dysfunction and free radical damage. Neurochem Int 62:1–7. https://doi.org/10.1016/j.neuint.2012.10.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Li H, Ham A, Ma TC, Kuo SH, Kanter E, Kim D, Ko HS, Quan Y, Sardi SP, Li A et al (2019) Mitochondrial dysfunction and mitophagy defect triggered by heterozygous GBA mutations. Autophagy 15:113–130. https://doi.org/10.1080/15548627.2018.1509818

    Article  CAS  PubMed  Google Scholar 

  59. Ivanova MM, Changsila E, Iaonou C, Goker-Alpan O (2019) Impaired autophagic and mitochondrial functions are partially restored by ERT in Gaucher and Fabry diseases. PLoS ONE 14:e0210617. https://doi.org/10.1371/journal.pone.0210617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Demaurex N, Frieden M, Arnaudeau S (2000–2013) ER calcium and ER chaperones: new players in apoptosis? Landes Bioscience, Austin (TX)

  61. Saffari A, Kölker S, Hoffmann GF, Ebrahimi-Fakhari D (2017) Linking mitochondrial dysfunction to neurodegeneration in lysosomal storage diseases. J Inherit Metab Dis 40:631–640. https://doi.org/10.1007/s10545-017-0048-0

    Article  CAS  PubMed  Google Scholar 

  62. Costa CAD, Manaa WE, Duplan E, Checler F (2020) The endoplasmic reticulum stress/unfolded protein response and their contributions to Parkinson’s disease physiopathology. Cells 9. https://doi.org/10.3390/cells9112495

  63. Deniaud A, Sharaf el dein O, Maillier E, Poncet D, Kroemer G, Lemaire C, Brenner C (2008) Endoplasmic reticulum stress induces calcium-dependent permeability transition, mitochondrial outer membrane permeabilization and apoptosis. Oncogene 27:285–299. https://doi.org/10.1038/sj.onc.1210638

    Article  CAS  PubMed  Google Scholar 

  64. Pelled D, Trajkovic-Bodennec S, Lloyd-Evans E, Sidransky E, Schiffmann R, Futerman AH (2005) Enhanced calcium release in the acute neuronopathic form of Gaucher disease. Neurobiol Dis 18:83–88. https://doi.org/10.1016/j.nbd.2004.09.004

    Article  CAS  PubMed  Google Scholar 

  65. Korkotian E, Schwarz A, Pelled D, Schwarzmann G, Segal M, Futerman AH (1999) Elevation of intracellular glucosylceramide levels results in an increase in endoplasmic reticulum density and in functional calcium stores in cultured neurons. J Biol Chem 274:21673–21678. https://doi.org/10.1074/jbc.274.31.21673

    Article  CAS  PubMed  Google Scholar 

  66. Raffaello A, Mammucari C, Gherardi G, Rizzuto R (2016) Calcium at the center of cell signaling: interplay between endoplasmic reticulum, mitochondria, and lysosomes. Trends Biochem Sci 41:1035–1049. https://doi.org/10.1016/j.tibs.2016.09.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Görlach A, Klappa P, Kietzmann T (2006) The endoplasmic reticulum: folding, calcium homeostasis, signaling, and redox control. Antioxid Redox Signal 8:1391–1418. https://doi.org/10.1089/ars.2006.8.1391

    Article  PubMed  Google Scholar 

  68. Plotegher N, Perocheau D, Ferrazza R, Massaro G, Bhosale G, Zambon F, Rahim AA, Guella G, Waddington SN, Szabadkai G et al (2020) Impaired cellular bioenergetics caused by GBA1 depletion sensitizes neurons to calcium overload. Cell Death Differ 27:1588–1603. https://doi.org/10.1038/s41418-019-0442-2

    Article  CAS  PubMed  Google Scholar 

  69. Chaudhari N, Talwar P, Parimisetty A, Lefebvre d’Hellencourt C, Ravanan P (2014) A molecular web: endoplasmic reticulum stress, inflammation, and oxidative stress. Front Cell Neurosci 8:213. https://doi.org/10.3389/fncel.2014.00213

    Article  PubMed  PubMed Central  Google Scholar 

  70. Atakpa P, Thillaiappan NB, Mataragka S, Prole DL, Taylor CW (2018) IP3 receptors preferentially associate with ER-lysosome contact sites and selectively deliver Ca2+ to lysosomes. Cell Rep 25:3180-3193.e3187. https://doi.org/10.1016/j.celrep.2018.11.064

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Peng W, Wong YC, Krainc D (2020) Mitochondria-lysosome contacts regulate mitochondrial Ca. Proc Natl Acad Sci U S A 117:19266–19275. https://doi.org/10.1073/pnas.2003236117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Liou B, Peng Y, Li R, Inskeep V, Zhang W, Quinn B, Dasgupta N, Blackwood R, Setchell KD, Fleming S et al (2016) Modulating ryanodine receptors with dantrolene attenuates neuronopathic phenotype in Gaucher disease mice. Hum Mol Genet 25:5126–5141. https://doi.org/10.1093/hmg/ddw322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Ghiglieri V, Calabrese V, Calabresi P (2018) Alpha-synuclein: from early synaptic dysfunction to neurodegeneration. Front Neurol 9:295. https://doi.org/10.3389/fneur.2018.00295

    Article  PubMed  PubMed Central  Google Scholar 

  74. Nakai M, Fujita M, Waragai M, Sugama S, Wei J, Akatsu H, Ohtaka-Maruyama C, Okado H, Hashimoto M (2007) Expression of alpha-synuclein, a presynaptic protein implicated in Parkinson’s disease, in erythropoietic lineage. Biochem Biophys Res Commun 358:104–110. https://doi.org/10.1016/j.bbrc.2007.04.108

    Article  CAS  PubMed  Google Scholar 

  75. Stojkovska I, Krainc D, Mazzulli JR (2018) Molecular mechanisms of α-synuclein and GBA1 in Parkinson’s disease. Cell Tissue Res 373:51–60. https://doi.org/10.1007/s00441-017-2704-y

    Article  CAS  PubMed  Google Scholar 

  76. Burré J, Sharma M, Südhof TC (2018) Cell biology and pathophysiology of α-synuclein. Cold Spring Harb Perspect Med 8. https://doi.org/10.1101/cshperspect.a024091

  77. Faustini G, Bono F, Valerio A, Pizzi M, Spano P, Bellucci A (2017) Mitochondria and α-synuclein: friends or foes in the pathogenesis of Parkinson’s disease? Genes (Basel) 8. https://doi.org/10.3390/genes8120377

  78. Lin KJ, Lin KL, Chen SD, Liou CW, Chuang YC, Lin HY, Lin TK (2019) The overcrowded crossroads: mitochondria, alpha-synuclein, and the endo-lysosomal system interaction in Parkinson’s disease. Int J Mol Sci 20. https://doi.org/10.3390/ijms20215312

  79. Shavali S, Brown-Borg HM, Ebadi M, Porter J (2008) Mitochondrial localization of alpha-synuclein protein in alpha-synuclein overexpressing cells. Neurosci Lett 439:125–128. https://doi.org/10.1016/j.neulet.2008.05.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Guardia-Laguarta C, Area-Gomez E, Rüb C, Liu Y, Magrané J, Becker D, Voos W, Schon EA, Przedborski S (2014) α-Synuclein is localized to mitochondria-associated ER membranes. J Neurosci 34:249–259. https://doi.org/10.1523/JNEUROSCI.2507-13.2014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Xu YH, Xu K, Sun Y, Liou B, Quinn B, Li RH, Xue L, Zhang W, Setchell KD, Witte D et al (2014) Multiple pathogenic proteins implicated in neuronopathic Gaucher disease mice. Hum Mol Genet 23:3943–3957. https://doi.org/10.1093/hmg/ddu105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Breydo L, Wu JW, Uversky VN (2012) Α-synuclein misfolding and Parkinson’s disease. Biochim Biophys Acta 1822:261–285. https://doi.org/10.1016/j.bbadis.2011.10.002

    Article  CAS  PubMed  Google Scholar 

  83. Pandey MK, Grabowski GA (2013) Immunological cells and functions in Gaucher disease. Crit Rev Oncog 18:197–220. https://doi.org/10.1615/critrevoncog.2013004503

    Article  PubMed  PubMed Central  Google Scholar 

  84. Auffray C, Sieweke MH, Geissmann F (2009) Blood monocytes: development, heterogeneity, and relationship with dendritic cells. Annu Rev Immunol 27:669–692. https://doi.org/10.1146/annurev.immunol.021908.132557

    Article  CAS  PubMed  Google Scholar 

  85. Serbina NV, Jia T, Hohl TM, Pamer EG (2008) Monocyte-mediated defense against microbial pathogens. Annu Rev Immunol 26:421–452. https://doi.org/10.1146/annurev.immunol.26.021607.090326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Allen MJ, Myer BJ, Khokher AM, Rushton N, Cox TM (1997) Pro-inflammatory cytokines and the pathogenesis of Gaucher’s disease: increased release of interleukin-6 and interleukin-10. QJM 90:19–25. https://doi.org/10.1093/qjmed/90.1.19

    Article  CAS  PubMed  Google Scholar 

  87. de Fost M, Out TA, de Wilde FA, Tjin EP, Pals ST, van Oers MH, Boot RG, Aerts JF, Maas M, Vom Dahl S et al (2008) Immunoglobulin and free light chain abnormalities in Gaucher disease type I: data from an adult cohort of 63 patients and review of the literature. Ann Hematol 87:439–449. https://doi.org/10.1007/s00277-008-0441-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Liu J, Halene S, Yang M, Iqbal J, Yang R, Mehal WZ, Chuang WL, Jain D, Yuen T, Sun L et al (2012) Gaucher disease gene GBA functions in immune regulation. Proc Natl Acad Sci U S A 109:10018–10023. https://doi.org/10.1073/pnas.1200941109

    Article  PubMed  PubMed Central  Google Scholar 

  89. Mizukami H, Mi Y, Wada R, Kono M, Yamashita T, Liu Y, Werth N, Sandhoff R, Sandhoff K, Proia RL (2002) Systemic inflammation in glucocerebrosidase-deficient mice with minimal glucosylceramide storage. J Clin Invest 109:1215–1221. https://doi.org/10.1172/JCI14530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. van Breemen MJ, de Fost M, Voerman JS, Laman JD, Boot RG, Maas M, Hollak CE, Aerts JM, Rezaee F (2007) Increased plasma macrophage inflammatory protein (MIP)-1alpha and MIP-1beta levels in type 1 Gaucher disease. Biochim Biophys Acta 1772:788–796. https://doi.org/10.1016/j.bbadis.2007.04.002

    Article  CAS  PubMed  Google Scholar 

  91. Guo H, Callaway JB, Ting JP (2015) Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med 21:677–687. https://doi.org/10.1038/nm.3893

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Eder C (2009) Mechanisms of interleukin-1beta release. Immunobiology 214:543–553. https://doi.org/10.1016/j.imbio.2008.11.007

    Article  CAS  PubMed  Google Scholar 

  93. Aflaki E, Moaven N, Borger DK, Lopez G, Westbroek W, Chae JJ, Marugan J, Patnaik S, Maniwang E, Gonzalez AN et al (2016) Lysosomal storage and impaired autophagy lead to inflammasome activation in Gaucher macrophages. Aging Cell 15:77–88. https://doi.org/10.1111/acel.12409

    Article  CAS  PubMed  Google Scholar 

  94. Janeway CAJ, Travers P, Walport M, Shlomchik MJ (2001) Immunobiology: the immune system in health and disease, 5th, edition. Garland Science, New York

    Google Scholar 

  95. Klos A, Wende E, Wareham KJ, Monk PN (2013) International Union of Basic and Clinical Pharmacology. [corrected]. LXXXVII. Complement peptide C5a, C4a, and C3a receptors. Pharmacol Rev 65:500–543. https://doi.org/10.1124/pr.111.005223

    Article  CAS  PubMed  Google Scholar 

  96. Pandey MK, Burrow TA, Rani R, Martin LJ, Witte D, Setchell KD, Mckay MA, Magnusen AF, Zhang W, Liou B et al (2017) Complement drives glucosylceramide accumulation and tissue inflammation in Gaucher disease. Nature 543:108–112. https://doi.org/10.1038/nature21368

    Article  CAS  PubMed  Google Scholar 

  97. Kolev M, Le Friec G, Kemper C (2014) Complement–tapping into new sites and effector systems. Nat Rev Immunol 14:811–820. https://doi.org/10.1038/nri3761

    Article  CAS  PubMed  Google Scholar 

  98. Kalluri R, LeBleu VS (2020) The biology, function, and biomedical applications of exosomes. Science 367. https://doi.org/10.1126/science.aau6977

  99. Raposo G, Stoorvogel W (2013) Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol 200:373–383. https://doi.org/10.1083/jcb.201211138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Gurung S, Perocheau D, Touramanidou L, Baruteau J (2021) The exosome journey: from biogenesis to uptake and intracellular signalling. Cell Commun Signal 19:47. https://doi.org/10.1186/s12964-021-00730-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Ciferri MC, Quarto R, Tasso R (2021) Extracellular vesicles as biomarkers and therapeutic tools: from pre-clinical to clinical applications. Biology (Basel) 10. https://doi.org/10.3390/biology10050359

  102. Zhang H, Lyden D (2019) Asymmetric-flow field-flow fractionation technology for exomere and small extracellular vesicle separation and characterization. Nat Protoc 14:1027–1053. https://doi.org/10.1038/s41596-019-0126-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Chan BD, Wong WY, Lee MM, Cho WC, Yee BK, Kwan YW, Tai WC (2019) Exosomes in inflammation and inflammatory disease. Proteomics 19:e1800149. https://doi.org/10.1002/pmic.201800149

    Article  CAS  PubMed  Google Scholar 

  104. LeBleu VS, Kalluri R (2020) Exosomes as a multicomponent biomarker platform in cancer. Trends Cancer 6:767–774. https://doi.org/10.1016/j.trecan.2020.03.007

    Article  CAS  PubMed  Google Scholar 

  105. Guo L, Huang Z, Huang L, Liang J, Wang P, Zhao L, Shi Y (2021) Surface-modified engineered exosomes attenuated cerebral ischemia/reperfusion injury by targeting the delivery of quercetin towards impaired neurons. J Nanobiotechnology 19:141. https://doi.org/10.1186/s12951-021-00879-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Tatiana S, Stanislav N, Darya K, Luiza G, Konstantin S, Sergey L, Elena V, Galina S, Nikolai V, Arthur K et al (2020) Altered level of plasma exosomes in patients with Gaucher disease. Eur J Med Genet 63:104038. https://doi.org/10.1016/j.ejmg.2020.104038

    Article  PubMed  Google Scholar 

  107. Papadopoulos VE, Nikolopoulou G, Antoniadou I, Karachaliou A, Arianoglou G, Emmanouilidou E, Sardi SP, Stefanis L, Vekrellis K (2018) Modulation of β-glucocerebrosidase increases α-synuclein secretion and exosome release in mouse models of Parkinson’s disease. Hum Mol Genet 27:1696–1710. https://doi.org/10.1093/hmg/ddy075

    Article  CAS  PubMed  Google Scholar 

  108. Bae EJ, Yang NY, Song M, Lee CS, Lee JS, Jung BC, Lee HJ, Kim S, Masliah E, Sardi SP et al (2014) Glucocerebrosidase depletion enhances cell-to-cell transmission of α-synuclein. Nat Commun 5:4755. https://doi.org/10.1038/ncomms5755

    Article  CAS  PubMed  Google Scholar 

  109. Johnson PH, Weinreb NJ, Cloyd JC, Tuite PJ, Kartha RV (2020) GBA1 mutations: prospects for exosomal biomarkers in α-synuclein pathologies. Mol Genet Metab 129:35–46. https://doi.org/10.1016/j.ymgme.2019.10.006

    Article  CAS  PubMed  Google Scholar 

  110. Cerri S, Ghezzi C, Sampieri M, Siani F, Avenali M, Dornini G, Zangaglia R, Minafra B, Blandini F (2018) The exosomal/total α-synuclein ratio in plasma is associated with glucocerebrosidase activity and correlates with measures of disease severity in PD patients. Front Cell Neurosci 12:125. https://doi.org/10.3389/fncel.2018.00125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Grey M, Dunning CJ, Gaspar R, Grey C, Brundin P, Sparr E, Linse S (2015) Acceleration of α-synuclein aggregation by exosomes. J Biol Chem 290:2969–2982. https://doi.org/10.1074/jbc.M114.585703

    Article  CAS  PubMed  Google Scholar 

  112. Essandoh K, Yang L, Wang X, Huang W, Qin D, Hao J, Wang Y, Zingarelli B, Peng T, Fan GC (2015) Blockade of exosome generation with GW4869 dampens the sepsis-induced inflammation and cardiac dysfunction. Biochim Biophys Acta 1852:2362–2371. https://doi.org/10.1016/j.bbadis.2015.08.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Abasolo I, Seras-Franzoso J, Moltó-Abad M, Díaz-Riascos V, Corchero JL, Pintos-Morell G, Schwartz S (2021) Nanotechnology-based approaches for treating lysosomal storage disorders, a focus on Fabry disease. Wiley Interdiscip Rev Nanomed Nanobiotechnol 13:e1684. https://doi.org/10.1002/wnan.1684

    Article  CAS  PubMed  Google Scholar 

  114. Wenstrup RJ, Roca-Espiau M, Weinreb NJ, Bembi B (2002) Skeletal aspects of Gaucher disease: a review. Br J Radiol 75(Suppl 1):A2-12. https://doi.org/10.1259/bjr.75.suppl_1.750002

    Article  PubMed  Google Scholar 

  115. Souza PP, Lerner UH (2013) The role of cytokines in inflammatory bone loss. Immunol Invest 42:555–622. https://doi.org/10.3109/08820139.2013.822766

    Article  CAS  PubMed  Google Scholar 

  116. Mucci JM, Rozenfeld P (2015) Pathogenesis of bone alterations in Gaucher disease: the role of immune system. J Immunol Res 2015:192761. https://doi.org/10.1155/2015/192761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Rozenfeld PA, Crivaro AN, Ormazabal M, Mucci JM, Bondar C, Delpino MV (2021) Unraveling the mystery of Gaucher bone density pathophysiology. Mol Genet Metab 132:76–85. https://doi.org/10.1016/j.ymgme.2020.07.011

    Article  CAS  PubMed  Google Scholar 

  118. Mucci JM, Rozenfeld PA (2014) Examining the impact of bone pathology on type I Gaucher disease. Clinical Lipidology 9:61–70. https://doi.org/10.2217/clp.13.78

    Article  CAS  Google Scholar 

  119. Okamoto K, Nakashima T, Shinohara M, Negishi-Koga T, Komatsu N, Terashima A, Sawa S, Nitta T, Takayanagi H (2017) Osteoimmunology: the conceptual framework unifying the immune and skeletal systems. Physiol Rev 97:1295–1349. https://doi.org/10.1152/physrev.00036.2016

    Article  CAS  PubMed  Google Scholar 

  120. Hollak CE, Evers L, Aerts JM, van Oers MH (1997) Elevated levels of M-CSF, sCD14 and IL8 in type 1 Gaucher disease. Blood Cells Mol Dis 23:201–212. https://doi.org/10.1006/bcmd.1997.0137

    Article  CAS  PubMed  Google Scholar 

  121. Xu Y, Yang F, Liu Y, Wang Z, Wang J, Wang G, Li R (2011) Genetic diversity of Microcystis populations in a bloom and its relationship to the environmental factors in Qinhuai River, China. Microbiol Res 167:20–26. https://doi.org/10.1016/j.micres.2011.02.005

    Article  CAS  PubMed  Google Scholar 

  122. Xu YH, Jia L, Quinn B, Zamzow M, Stringer K, Aronow B, Sun Y, Zhang W, Setchell KD, Grabowski GA (2011) Global gene expression profile progression in Gaucher disease mouse models. BMC Genomics 12:20. https://doi.org/10.1186/1471-2164-12-20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Abe M, Hiura K, Wilde J, Moriyama K, Hashimoto T, Ozaki S, Wakatsuki S, Kosaka M, Kido S, Inoue D et al (2002) Role for macrophage inflammatory protein (MIP)-1alpha and MIP-1beta in the development of osteolytic lesions in multiple myeloma. Blood 100:2195–2202

    Article  CAS  PubMed  Google Scholar 

  124. Mistry PK, Liu J, Sun L, Chuang WL, Yuen T, Yang R, Lu P, Zhang K, Li J, Keutzer J et al (2014) Glucocerebrosidase 2 gene deletion rescues type 1 Gaucher disease. Proc Natl Acad Sci U S A 111:4934–4939. https://doi.org/10.1073/pnas.1400768111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Zhang Q, Chen B, Yan F, Guo J, Zhu X, Ma S, Yang W (2014) Interleukin-10 inhibits bone resorption: a potential therapeutic strategy in periodontitis and other bone loss diseases. Biomed Res Int 2014:284836. https://doi.org/10.1155/2014/284836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Yoshino M, Watanabe Y, Tokunaga Y, Harada E, Fujii C, Numata S, Harada M, Tajima A, Ida H (2007) Roles of specific cytokines in bone remodeling and hematopoiesis in Gaucher disease. Pediatr Int 49:959–965. https://doi.org/10.1111/j.1442-200X.2007.02502.x

    Article  CAS  PubMed  Google Scholar 

  127. Khan A, Hangartner T, Weinreb NJ, Taylor JS, Mistry PK (2012) Risk factors for fractures and avascular osteonecrosis in type 1 Gaucher disease: a study from the International Collaborative Gaucher Group (ICGG) Gaucher Registry. J Bone Miner Res 27:1839–1848. https://doi.org/10.1002/jbmr.1680

    Article  PubMed  Google Scholar 

  128. Maas M, Hollak CE, Akkerman EM, Aerts JM, Stoker J, Den Heeten GJ (2002) Quantification of skeletal involvement in adults with type I Gaucher’s disease: fat fraction measured by Dixon quantitative chemical shift imaging as a valid parameter. AJR Am J Roentgenol 179:961–965. https://doi.org/10.2214/ajr.179.4.1790961

    Article  PubMed  Google Scholar 

  129. Li D, Tao X, Zhang N, Huo A, Kang H, Xu C, Zhang Y, Peng Y (2020) Do magnetic resonance imaging manifestations of skeletal system improve after treatment of Gaucher disease? Eur J Radiol 125:108851. https://doi.org/10.1016/j.ejrad.2020.108851

    Article  PubMed  Google Scholar 

  130. Mistry PK, Deegan P, Vellodi A, Cole JA, Yeh M, Weinreb NJ (2009) Avascular necrosis in untreated patients with type 1 Gaucher disease blood

  131. Bell RS, Mankin HJ, Doppelt SH (1986) Osteomyelitis in Gaucher disease. J Bone Joint Surg Am 68:1380–1388

    Article  CAS  PubMed  Google Scholar 

  132. Giraldo P, Solano V, Pérez-Calvo JI, Giralt M, Rubio-Félix D, disease SGoG (2005) Quality of life related to type 1 Gaucher disease: Spanish experience. Qual Life Res 14:453–462. https://doi.org/10.1007/s11136-004-0794-y

    Article  PubMed  Google Scholar 

  133. Lutsky KF, Tejwani NC (2007) Orthopaedic manifestations of Gaucher disease. Bull NYU Hosp Jt Dis 65:37–42

    PubMed  Google Scholar 

  134. Binnetoglu E, Komurcu E, Sen H, Kizildag B (2013) Gaucher disease with pathological femoral neck fracture. BMJ Case Rep 2013. https://doi.org/10.1136/bcr-2013-200260

  135. Hong JM, Kim TH, Kim HJ, Park EK, Yang EK, Kim SY (2010) Genetic association of angiogenesis- and hypoxia-related gene polymorphisms with osteonecrosis of the femoral head. Exp Mol Med 42:376–385. https://doi.org/10.3858/emm.2010.42.5.039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Linari S, Castaman G (2015) Clinical manifestations and management of Gaucher disease. Clin Cases Miner Bone Metab 12:157–164. https://doi.org/10.11138/ccmbm/2015.12.2.157

    Article  PubMed  PubMed Central  Google Scholar 

  137. Goodman SB, Maruyama M (2020) Inflammation, bone healing and osteonecrosis: from bedside to bench. J Inflamm Res 13:913–923. https://doi.org/10.2147/JIR.S281941

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Schmidt T, Carmeliet P (2011) Angiogenesis: a target in solid tumors, also in leukemia? Hematology Am Soc Hematol Educ Program 2011:1–8. https://doi.org/10.1182/asheducation-2011.1.1

    Article  PubMed  Google Scholar 

  139. Weinreb NJ, Finegold DN, Feingold E, Zeng Z, Rosenbloom BE, Shankar SP, Amato D (2015) Evaluation of disease burden and response to treatment in adults with type 1 Gaucher disease using a validated disease severity scoring system (DS3). Orphanet J Rare Dis 10:64. https://doi.org/10.1186/s13023-015-0280-3

    Article  PubMed  PubMed Central  Google Scholar 

  140. Neudorfer O, Giladi N, Elstein D, Abrahamov A, Turezkite T, Aghai E, Reches A, Bembi B, Zimran A (1996) Occurrence of Parkinson’s syndrome in type I Gaucher disease. QJM 89:691–694. https://doi.org/10.1093/qjmed/89.9.691

    Article  CAS  PubMed  Google Scholar 

  141. Machaczka M, Rucinska M, Skotnicki AB, Jurczak W (1999) Parkinson’s syndrome preceding clinical manifestation of Gaucher’s disease. Am J Hematol 61:216–217. https://doi.org/10.1002/(sici)1096-8652(199907)61:3%3c216::aid-ajh12%3e3.0.co;2-b

    Article  CAS  PubMed  Google Scholar 

  142. Tayebi N, Callahan M, Madike V, Stubblefield BK, Orvisky E, Krasnewich D, Fillano JJ, Sidransky E (2001) Gaucher disease and parkinsonism: a phenotypic and genotypic characterization. Mol Genet Metab 73:313–321. https://doi.org/10.1006/mgme.2001.3201

    Article  CAS  PubMed  Google Scholar 

  143. Várkonyi J, Rosenbaum H, Baumann N, MacKenzie JJ, Simon Z, Aharon-Peretz J, Walker JM, Tayebi N, Sidransky E (2003) Gaucher disease associated with parkinsonism: four further case reports. Am J Med Genet A 116A:348–351. https://doi.org/10.1002/ajmg.a.10028

    Article  PubMed  Google Scholar 

  144. Bembi B, Zambito Marsala S, Sidransky E, Ciana G, Carrozzi M, Zorzon M, Martini C, Gioulis M, Pittis MG, Capus L (2003) Gaucher’s disease with Parkinson’s disease: clinical and pathological aspects. Neurology 61:99–101. https://doi.org/10.1212/01.wnl.0000072482.70963.d7

    Article  CAS  PubMed  Google Scholar 

  145. Aharon-Peretz J, Rosenbaum H, Gershoni-Baruch R (2004) Mutations in the glucocerebrosidase gene and Parkinson’s disease in Ashkenazi Jews. N Engl J Med 351:1972–1977. https://doi.org/10.1056/NEJMoa033277

    Article  CAS  PubMed  Google Scholar 

  146. Lwin A, Orvisky E, Goker-Alpan O, LaMarca ME, Sidransky E (2004) Glucocerebrosidase mutations in subjects with parkinsonism. Mol Genet Metab 81:70–73. https://doi.org/10.1016/j.ymgme.2003.11.004

    Article  CAS  PubMed  Google Scholar 

  147. Schapira AH (2015) Glucocerebrosidase and Parkinson disease: recent advances. Mol Cell Neurosci 66:37–42. https://doi.org/10.1016/j.mcn.2015.03.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, Barbosa ER, Bar-Shira A, Berg D, Bras J, Brice A et al (2009) Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease. N Engl J Med 361:1651–1661. https://doi.org/10.1056/NEJMoa0901281

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Ryan E, Amato D, MacKenzie JJ, Sidransky E, Lopez G (2020) Parkinsonism in Patients with neuronopathic (type 3) Gaucher disease: a case series. Mov Disord Clin Pract 7:834–837. https://doi.org/10.1002/mdc3.13031

    Article  PubMed  PubMed Central  Google Scholar 

  150. Schapira AH, Tolosa E (2010) Molecular and clinical prodrome of Parkinson disease: implications for treatment. Nat Rev Neurol 6:309–317. https://doi.org/10.1038/nrneurol.2010.52

    Article  CAS  PubMed  Google Scholar 

  151. Mazzulli JR, Xu YH, Sun Y, Knight AL, McLean PJ, Caldwell GA, Sidransky E, Grabowski GA, Krainc D (2011) Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell 146:37–52. https://doi.org/10.1016/j.cell.2011.06.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Kim GH, Kim JE, Rhie SJ, Yoon S (2015) The role of oxidative stress in neurodegenerative diseases. Exp Neurobiol 24:325–340. https://doi.org/10.5607/en.2015.24.4.325

    Article  PubMed  PubMed Central  Google Scholar 

  153. Wang X, Michaelis EK (2010) Selective neuronal vulnerability to oxidative stress in the brain. Front Aging Neurosci 2:12. https://doi.org/10.3389/fnagi.2010.00012

    Article  PubMed  PubMed Central  Google Scholar 

  154. Ferreira ME, de Vasconcelos AS, da Costa VT, da Silva TL, da Silva BA, Gomes AR, Dolabela MF, Percário S (2015) Oxidative stress in Alzheimer’s disease: should we keep trying antioxidant therapies? Cell Mol Neurobiol 35:595–614. https://doi.org/10.1007/s10571-015-0157-y

    Article  CAS  PubMed  Google Scholar 

  155. Block ML, Zecca L, Hong JS (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8:57–69. https://doi.org/10.1038/nrn2038

    Article  CAS  PubMed  Google Scholar 

  156. Blesa J, Trigo-Damas I, Quiroga-Varela A, Jackson-Lewis VR (2015) Oxidative stress and Parkinson’s disease. Front Neuroanat 9:91. https://doi.org/10.3389/fnana.2015.00091

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Gagne JJ, Power MC (2010) Anti-inflammatory drugs and risk of Parkinson disease: a meta-analysis. Neurology 74:995–1002. https://doi.org/10.1212/WNL.0b013e3181d5a4a3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Rachsee A, Chiranthanut N, Kunnaja P, Sireeratawong S, Khonsung P, Chansakaow S, Panthong A (2021) Mucuna pruriens (L.) DC. seed extract inhibits lipopolysaccharide-induced inflammatory responses in BV2 microglial cells. J Ethnopharmacol 267:113518. https://doi.org/10.1016/j.jep.2020.113518

  159. Javed H, Meeran MFN, Azimullah S, Bader Eddin L, Dwivedi VD, Jha NK, Ojha S (2020) α-Bisabolol, a dietary bioactive phytochemical attenuates dopaminergic neurodegeneration through modulation of oxidative stress, neuroinflammation and apoptosis in rotenone-induced rat model of Parkinson’s disease. Biomolecules 10. https://doi.org/10.3390/biom10101421

  160. Tian Y, Cao Y, Chen R, Jing Y, Xia L, Zhang S, Xu H, Su Z (2020) HMGB1 a box protects neurons by potently inhibiting both microglia and T cell-mediated inflammation in a mouse Parkinson’s disease model. Clin Sci (Lond) 134:2075–2090. https://doi.org/10.1042/CS20200553

    Article  CAS  Google Scholar 

  161. Egger F, Jakab M, Fuchs J, Oberascher K, Brachtl G, Ritter M, Kerschbaum HH, Gaisberger M (2020) Effect of glycine on BV-2 microglial cells treated with interferon-γ and lipopolysaccharide. Int J Mol Sci 21. https://doi.org/10.3390/ijms21030804

  162. Chen X, Hu Y, Cao Z, Liu Q, Cheng Y (2018) Cerebrospinal fluid inflammatory cytokine aberrations in Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis: a systematic review and meta-analysis. Front Immunol 9:2122. https://doi.org/10.3389/fimmu.2018.02122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Galper J, Balwani M, Fahn S, Waters C, Krohn L, Gan-Or Z, Dzamko N, Alcalay RN (2021) Cytokines and Gaucher biomarkers in glucocerebrosidase carriers with and without Parkinson disease. Mov Disord. https://doi.org/10.1002/mds.28525

  164. Mullin S, Hughes D, Mehta A, Schapira AHV (2019) Neurological effects of glucocerebrosidase gene mutations. Eur J Neurol 26:388-e329. https://doi.org/10.1111/ene.13837

    Article  CAS  PubMed  Google Scholar 

  165. Valdés P, Mercado G, Vidal RL, Molina C, Parsons G, Court FA, Martinez A, Galleguillos D, Armentano D, Schneider BL et al (2014) Control of dopaminergic neuron survival by the unfolded protein response transcription factor XBP1. Proc Natl Acad Sci U S A 111:6804–6809. https://doi.org/10.1073/pnas.1321845111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Zimran A (2011) How I treat Gaucher disease Blood 118:1463–1471. https://doi.org/10.1182/blood-2011-04-308890

    Article  CAS  Google Scholar 

  167. Barton NW, Brady RO, Dambrosia JM, Di Bisceglie AM, Doppelt SH, Hill SC, Mankin HJ, Murray GJ, Parker RI, Argoff CE (1991) Replacement therapy for inherited enzyme deficiency–macrophage-targeted glucocerebrosidase for Gaucher’s disease. N Engl J Med 324:1464–1470. https://doi.org/10.1056/NEJM199105233242104

    Article  CAS  PubMed  Google Scholar 

  168. Zhang XS, Brondyk W, Lydon JT, Thurberg BL, Piepenhagen PA (2011) Biotherapeutic target or sink: analysis of the macrophage mannose receptor tissue distribution in murine models of lysosomal storage diseases. J Inherit Metab Dis 34:795–809. https://doi.org/10.1007/s10545-011-9285-9

    Article  CAS  PubMed  Google Scholar 

  169. Mistry PK, Wraight EP, Cox TM (1996) Therapeutic delivery of proteins to macrophages: implications for treatment of Gaucher’s disease. Lancet 348:1555–1559. https://doi.org/10.1016/S0140-6736(96)04451-0

    Article  CAS  PubMed  Google Scholar 

  170. Beutler E, Kay AC, Saven A, Garver P, Thurston DW, Rosenbloom BE (1991) Enzyme-replacement therapy for Gaucher’s disease. New England J Medicine 325:1809–1811. https://doi.org/10.1056/nejm199112193252513

  171. Rosenbloom BE, Weinreb NJ (2014) Bone disease in patients with Gaucher disease. Expert Rev Endocrinol Metab 9:153–162. https://doi.org/10.1586/17446651.2014.887434

    Article  CAS  PubMed  Google Scholar 

  172. Hollak CE, Levi M, Berends F, Aerts JM, van Oers MH (1997) Coagulation abnormalities in type 1 Gaucher disease are due to low-grade activation and can be partly restored by enzyme supplementation therapy. Br J Haematol 96:470–476. https://doi.org/10.1046/j.1365-2141.1997.d01-2076.x

    Article  CAS  PubMed  Google Scholar 

  173. Sturtzel C (2017) Endothelial Cells. Adv Exp Med Biol 1003:71–91. https://doi.org/10.1007/978-3-319-57613-8_4

    Article  CAS  PubMed  Google Scholar 

  174. Pober JS, Sessa WC (2007) Evolving functions of endothelial cells in inflammation. Nat Rev Immunol 7:803–815. https://doi.org/10.1038/nri2171

    Article  CAS  PubMed  Google Scholar 

  175. Oto Y, Inoue T, Nagai S, Tanaka S, Itabashi H, Shiraisihi M, Nitta A, Murakami N, Ida H, Matsubara T (2021) Successful treatment of Gaucher disease type 1 by enzyme replacement therapy over a 10-year duration in a Japanese pediatric patient: a case report. Exp Ther Med 21:246. https://doi.org/10.3892/etm.2021.9677

    Article  PubMed  PubMed Central  Google Scholar 

  176. Matsubara C, Yamamoto K, Maeda T, Itakura J, Uehara T, Shiote Y, Adachi K, Kamoi C, Oyama T, Shiraishi Y et al (2020) Successful treatment with enzyme replacement therapy for pelvic fragile fracture in an elderly case of type I Gaucher’s disease. Rinsho Ketsueki 61:1654–1659. https://doi.org/10.11406/rinketsu.61.1654

    Article  PubMed  Google Scholar 

  177. Gupta P, Pastores G (2018) Pharmacological treatment of pediatric Gaucher disease. Expert Rev Clin Pharmacol 11:1183–1194. https://doi.org/10.1080/17512433.2018.1549486

    Article  CAS  PubMed  Google Scholar 

  178. Revel-Vilk S, Szer J, Mehta A, Zimran A (2018) How we manage Gaucher disease in the era of choices. Br J Haematol 182:467–480. https://doi.org/10.1111/bjh.15402

    Article  PubMed  Google Scholar 

  179. Shawky RM, Elsayed SM (2016) Treatment options for patients with Gaucher disease. Egyptian Journal of Medical Human Genetics 17:281–285

    Article  Google Scholar 

  180. Venier RE, Igdoura SA (2012) Miglustat as a therapeutic agent: prospects and caveats. J Med Genet 49:591–597. https://doi.org/10.1136/jmedgenet-2012-101070

    Article  CAS  PubMed  Google Scholar 

  181. Shayman JA (2010) Eliglustat tartrate: glucosylceramide synthase inhibitor treatment of type 1 Gaucher disease. Drugs Future 35:613–620

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Cox TM, Aerts JM, Andria G, Beck M, Belmatoug N, Bembi B, Chertkoff R, Vom Dahl S, Elstein D, Erikson A et al (2003) The role of the iminosugar N-butyldeoxynojirimycin (miglustat) in the management of type I (non-neuronopathic) Gaucher disease: a position statement. J Inherit Metab Dis 26:513–526. https://doi.org/10.1023/a:1025902113005

    Article  CAS  PubMed  Google Scholar 

  183. Elstein D, Dweck A, Attias D, Hadas-Halpern I, Zevin S, Altarescu G, Aerts JF, van Weely S, Zimran A (2007) Oral maintenance clinical trial with miglustat for type I Gaucher disease: switch from or combination with intravenous enzyme replacement. Blood 110:2296–2301. https://doi.org/10.1182/blood-2007-02-075960

    Article  CAS  PubMed  Google Scholar 

  184. Mistry PK, Lukina E, Ben Turkia H, Shankar SP, Baris H, Ghosn M, Mehta A, Packman S, Pastores G, Petakov M et al (2017) Outcomes after 18 months of eliglustat therapy in treatment-naïve adults with Gaucher disease type 1: the phase 3 ENGAGE trial. Am J Hematol 92:1170–1176. https://doi.org/10.1002/ajh.24877

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Limgala RP, Goker-Alpan O (2020) Effect of substrate reduction therapy in comparison to enzyme replacement therapy on immune aspects and bone involvement in Gaucher disease. Biomolecules 10. https://doi.org/10.3390/biom10040526

  186. Nabizadeh A, Amani B, Kadivar M, Toroski M, Asl AA, Bayazidi Y, Mojahedian M, Davari M (2018) The clinical efficacy of imiglucerase versus eliglustat in patients with Gaucher’s disease type 1: a systematic review. J Res Pharm Pract 7:171–177. https://doi.org/10.4103/jrpp.JRPP_18_24

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Bennett LL, Fellner C (2018) Pharmacotherapy of Gaucher disease: current and future options. P T 43:274–309

    PubMed  PubMed Central  Google Scholar 

  188. Wenstrup RJ, Kacena KA, Kaplan P, Pastores GM, Prakash-Cheng A, Zimran A, Hangartner TN (2007) Effect of enzyme replacement therapy with imiglucerase on BMD in type 1 Gaucher disease. J Bone Miner Res 22:119–126. https://doi.org/10.1359/jbmr.061004

    Article  CAS  PubMed  Google Scholar 

  189. Weinreb NJ, Goldblatt J, Villalobos J, Charrow J, Cole JA, Kerstenetzky M, vom Dahl S, Hollak C (2013) Long-term clinical outcomes in type 1 Gaucher disease following 10 years of imiglucerase treatment. J Inherit Metab Dis 36:543–553. https://doi.org/10.1007/s10545-012-9528-4

    Article  CAS  PubMed  Google Scholar 

  190. Weinreb NJ, Camelo JS, Charrow J, McClain MR, Mistry P, Belmatoug N, investigators ICGGIGRN (2021) Gaucher disease type 1 patients from the ICGG Gaucher registry sustain initial clinical improvements during twenty years of imiglucerase treatment. Mol Genet Metab 132:100–111. https://doi.org/10.1016/j.ymgme.2020.12.295

    Article  CAS  PubMed  Google Scholar 

  191. Potnis KC, Flueckinger LB, Ha CI, Upadia J, Frush DP, Kishnani PS (2019) Bone manifestations in neuronopathic Gaucher disease while receiving high-dose enzyme replacement therapy. Mol Genet Metab 126:157–161. https://doi.org/10.1016/j.ymgme.2018.11.004

    Article  CAS  PubMed  Google Scholar 

  192. Deegan PB, Pavlova E, Tindall J, Stein PE, Bearcroft P, Mehta A, Hughes D, Wraith JE, Cox TM (2011) Osseous manifestations of adult Gaucher disease in the era of enzyme replacement therapy. Medicine (Baltimore) 90:52–60. https://doi.org/10.1097/MD.0b013e3182057be4

    Article  CAS  Google Scholar 

  193. Shani M, Lustman A, Vinker S (2019) Adherence to oral antihypertensive medications, are all medications equal? J Clin Hypertens (Greenwich) 21:243–248. https://doi.org/10.1111/jch.13475

    Article  CAS  Google Scholar 

  194. Cramer JA (2004) A systematic review of adherence with medications for diabetes. Diabetes Care 27:1218–1224. https://doi.org/10.2337/diacare.27.5.1218

    Article  PubMed  Google Scholar 

  195. Medicine NLo (2018) Safety and efficacy of eliglustat with or without imiglucerase in pediatric patients with Gaucher disease (GD) type 1 and type 3 (ELIKIDS)

  196. Kane MK, Dean L (2020) Eliglustat therapy and CYP2D6 genotype National Center for Biotechnology Information (US), Bethesda (MD)

  197. Brady RO, Yang C, Zhuang Z (2013) An innovative approach to the treatment of Gaucher disease and possibly other metabolic disorders of the brain. J Inherit Metab Dis 36:451–454. https://doi.org/10.1007/s10545-012-9515-9

    Article  CAS  PubMed  Google Scholar 

  198. Eisengart JB, Pierpont EI, Kaizer AM, Rudser KD, King KE, Pasquali M, Polgreen LE, Dickson PI, Le SQ, Miller WP et al (2019) Intrathecal enzyme replacement for Hurler syndrome: biomarker association with neurocognitive outcomes. Genet Med 21:2552–2560. https://doi.org/10.1038/s41436-019-0522-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Cherukuri A, Cahan H, de Hart G, Van Tuyl A, Slasor P, Bray L, Henshaw J, Ajayi T, Jacoby D, O’Neill CA et al (2018) Immunogenicity to cerliponase alfa intracerebroventricular enzyme replacement therapy for CLN2 disease: results from a phase 1/2 study. Clin Immunol 197:68–76. https://doi.org/10.1016/j.clim.2018.09.003

    Article  CAS  PubMed  Google Scholar 

  200. Hollak CE, Aerts JM, Goudsmit R, Phoa SS, Ek M, van Weely S, von dem Borne AE, van Oers MH (1995) Individualised low-dose alglucerase therapy for type 1 Gaucher’s disease. Lancet 345:1474–1478. https://doi.org/10.1016/s0140-6736(95)91037-9

    Article  CAS  PubMed  Google Scholar 

  201. Larsen SD, Wilson MW, Abe A, Shu L, George CH, Kirchhoff P, Showalter HD, Xiang J, Keep RF, Shayman JA (2012) Property-based design of a glucosylceramide synthase inhibitor that reduces glucosylceramide in the brain. J Lipid Res 53:282–291. https://doi.org/10.1194/jlr.M021261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Platt FM, Jeyakumar M, Andersson U, Heare T, Dwek RA, Butters TD (2003) Substrate reduction therapy in mouse models of the glycosphingolipidoses. Philos Trans R Soc Lond B Biol Sci 358:947–954. https://doi.org/10.1098/rstb.2003.1279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Schiffmann R, Fitzgibbon EJ, Harris C, DeVile C, Davies EH, Abel L, van Schaik IN, Benko W, Timmons M, Ries M et al (2008) Randomized, controlled trial of miglustat in Gaucher’s disease type 3. Ann Neurol 64:514–522. https://doi.org/10.1002/ana.21491

    Article  PubMed  PubMed Central  Google Scholar 

  204. Shayman JA (2013) The design and clinical development of inhibitors of glycosphingolipid synthesis: will invention be the mother of necessity? Trans Am Clin Climatol Assoc 124:46–60

    PubMed  PubMed Central  Google Scholar 

  205. Balwani M, Burrow TA, Charrow J, Goker-Alpan O, Kaplan P, Kishnani PS, Mistry P, Ruskin J, Weinreb N (2016) Recommendations for the use of eliglustat in the treatment of adults with Gaucher disease type 1 in the United States. Mol Genet Metab 117:95–103. https://doi.org/10.1016/j.ymgme.2015.09.002

    Article  CAS  PubMed  Google Scholar 

  206. Peterschmitt MJ, Burke A, Blankstein L, Smith SE, Puga AC, Kramer WG, Harris JA, Mathews D, Bonate PL (2011) Safety, tolerability, and pharmacokinetics of eliglustat tartrate (Genz-112638) after single doses, multiple doses, and food in healthy volunteers. J Clin Pharmacol 51:695–705. https://doi.org/10.1177/0091270010372387

    Article  CAS  PubMed  Google Scholar 

  207. Peterschmitt MJ, Freisens S, Underhill LH, Foster MC, Lewis G, Gaemers SJM (2019) Long-term adverse event profile from four completed trials of oral eliglustat in adults with Gaucher disease type 1. Orphanet J Rare Dis 14:128. https://doi.org/10.1186/s13023-019-1085-6

    Article  PubMed  PubMed Central  Google Scholar 

  208. Marshall J, Sun Y, Bangari DS, Budman E, Park H, Nietupski JB, Allaire A, Cromwell MA, Wang B, Grabowski GA et al (2016) CNS-accessible inhibitor of glucosylceramide synthase for substrate reduction therapy of neuronopathic Gaucher disease. Mol Ther 24:1019–1029. https://doi.org/10.1038/mt.2016.53

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Schiffmann R, Cox T, Dedieu J-F, Sebastiaan G, Hennermann JB, Ida H, Mengel E, Mistry PK, Musholt PB, Sharma J et al (2021) Venglustat combined with imiglucerase positively affects neurological features and brain connectivity in adults with Gaucher disease type 3. Mol Genet Metab 132:S95

    Article  Google Scholar 

  210. Hobkirk R, Nilsen M, Purre E (1966) Peripheral interconversion of phenolic steroids in the human. Can J Biochem 44:1211–1220. https://doi.org/10.1139/o66-138

    Article  CAS  PubMed  Google Scholar 

  211. Weber G, Henry MC, Wagle SR, Wagle DS (1964) Correlation of enzyme activities and metabolic pathways with growth rate of hepatomas. Adv Enzyme Regul 2:335–346. https://doi.org/10.1016/s0065-2571(64)80024-8

    Article  CAS  PubMed  Google Scholar 

  212. Blum A (n.d.) Gene therapy for Gaucher disease: AAV, Lentivirus, & MoreNational Gaucher Foundation. https://www.gaucherdisease.org/blog/gene-therapy-for-gaucher-disease-aav-lentivirus-more/ Accessed 26 April 2021

  213. Maegawa GH, Tropak MB, Buttner JD, Rigat BA, Fuller M, Pandit D, Tang L, Kornhaber GJ, Hamuro Y, Clarke JT et al (2009) Identification and characterization of ambroxol as an enzyme enhancement agent for Gaucher disease. J Biol Chem 284:23502–23516. https://doi.org/10.1074/jbc.M109.012393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Migdalska-Richards A, Ko WKD, Li Q, Bezard E, Schapira AHV (2017) Oral ambroxol increases brain glucocerebrosidase activity in a nonhuman primate. Synapse 71. https://doi.org/10.1002/syn.21967

  215. McNeill A, Magalhaes J, Shen C, Chau KY, Hughes D, Mehta A, Foltynie T, Cooper JM, Abramov AY, Gegg M et al (2014) Ambroxol improves lysosomal biochemistry in glucocerebrosidase mutation-linked Parkinson disease cells. Brain 137:1481–1495. https://doi.org/10.1093/brain/awu020

    Article  PubMed  PubMed Central  Google Scholar 

  216. Luan Z, Li L, Higaki K, Nanba E, Suzuki Y, Ohno K (2013) The chaperone activity and toxicity of ambroxol on Gaucher cells and normal mice. Brain Dev 35:317–322. https://doi.org/10.1016/j.braindev.2012.05.008

    Article  PubMed  Google Scholar 

  217. Istaiti M, Revel-Vilk S, Becker-Cohen M, Dinur T, Ramaswami U, Castillo-Garcia D, Ceron-Rodriguez M, Chan A, Rodic P, Tincheva RS et al (2021) Upgrading the evidence for the use of ambroxol in Gaucher disease and GBA related Parkinson: investigator initiated registry based on real life data. Am J Hematol. https://doi.org/10.1002/ajh.26131

  218. Narita A, Shirai K, Itamura S, Matsuda A, Ishihara A, Matsushita K, Fukuda C, Kubota N, Takayama R, Shigematsu H et al (2016) Ambroxol chaperone therapy for neuronopathic Gaucher disease: a pilot study. Ann Clin Transl Neurol 3:200–215. https://doi.org/10.1002/acn3.292

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Pawlinski L, Krawczyk M, Fiema M, Tobor E, Kiec-Wilk B (2020) Dual-action ambroxol in treatment of chronic pain in Gaucher disease. Eur J Pain 24:992–996. https://doi.org/10.1002/ejp.1538

    Article  CAS  PubMed  Google Scholar 

  220. Chu SY, Chien CC, Hwu WL, Wang PJ, Chien YH (2020) Early initiation of high-dose oral ambroxol in combination with enzyme replacement therapy in a neuropathic Gaucher infant. Blood Cells Mol Dis 81:102402. https://doi.org/10.1016/j.bcmd.2019.102402

    Article  CAS  PubMed  Google Scholar 

  221. Jiang W, Yi M, Maegawa GHB, Zhang H (2020) Ambroxol improves skeletal and hematological manifestations on a child with Gaucher disease. J Hum Genet 65:345–349. https://doi.org/10.1038/s10038-019-0704-3

    Article  PubMed  Google Scholar 

  222. Kirkegaard T, Gray J, Priestman DA, Wallom KL, Atkins J, Olsen OD, Klein A, Drndarski S, Petersen NH, Ingemann L et al (2016) Heat shock protein-based therapy as a potential candidate for treating the sphingolipidoses. Sci Transl Med 8:355ra118. https://doi.org/10.1126/scitranslmed.aad9823

  223. Fog CK, Zago P, Malini E, Solanko LM, Peruzzo P, Bornaes C, Magnoni R, Mehmedbasic A, Petersen NHT, Bembi B et al (2018) The heat shock protein amplifier arimoclomol improves refolding, maturation and lysosomal activity of glucocerebrosidase. EBioMedicine 38:142–153. https://doi.org/10.1016/j.ebiom.2018.11.037

    Article  PubMed  PubMed Central  Google Scholar 

  224. Radke V (2021) FDA denies approval of arimoclomol for the treatment of Niemann-Pick type C check rare

  225. Hennermann JB, Gökce S, Solyom A, Mengel E, Schuchman EH, Simonaro CM (2016) Treatment with pentosan polysulphate in patients with MPS I: results from an open label, randomized, monocentric phase II study. J Inherit Metab Dis 39:831–837. https://doi.org/10.1007/s10545-016-9974-5

    Article  CAS  PubMed  Google Scholar 

  226. Crivaro AN, Mucci JM, Bondar CM, Ormazabal ME, Ceci R, Simonaro C, Rozenfeld PA (2019) Efficacy of pentosan polysulfate in in vitro models of lysosomal storage disorders: Fabry and Gaucher disease. PLoS ONE 14:e0217780. https://doi.org/10.1371/journal.pone.0217780

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Dean O, Giorlando F, Berk M (2011) N-acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action. J Psychiatry Neurosci 36:78–86. https://doi.org/10.1503/jpn.100057

    Article  PubMed  PubMed Central  Google Scholar 

  228. Whillier S, Raftos JE, Chapman B, Kuchel PW (2009) Role of N-acetylcysteine and cystine in glutathione synthesis in human erythrocytes. Redox Rep 14:115–124. https://doi.org/10.1179/135100009X392539

    Article  CAS  PubMed  Google Scholar 

  229. Holmay MJ, Terpstra M, Coles LD, Mishra U, Ahlskog M, Öz G, Cloyd JC, Tuite PJ (2013) N-Acetylcysteine boosts brain and blood glutathione in Gaucher and Parkinson diseases. Clin Neuropharmacol 36:103–106. https://doi.org/10.1097/WNF.0b013e31829ae713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Coles LD, Tuite PJ, Öz G, Mishra UR, Kartha RV, Sullivan KM, Cloyd JC, Terpstra M (2018) Repeated-dose oral N-acetylcysteine in Parkinson’s disease: pharmacokinetics and effect on brain glutathione and oxidative stress. J Clin Pharmacol 58:158–167. https://doi.org/10.1002/jcph.1008

    Article  CAS  PubMed  Google Scholar 

  231. Kartha RV, Joers J, Terluk M, Tuite P, Mishra U, Rudser K, Oz G, Weinreb NJ, Jarnes-Utz J, Cloyd JC (2019) Preliminary N-acetylcysteine results for LDN 6722 - role of oxidative stress and inflammation in Gaucher disease type 1: potential use of antioxidant anti-inflammatory medications. Mol Genet Metab 126:S82. https://doi.org/10.1016/j.ymgme.2018.12.201

    Article  Google Scholar 

  232. Kartha RV, Terluk M, Kumar T, Zayed H, Doss GP, Cloyd J (2020) Synergistic chaperone activity of N-acetylcysteine and its metabolite L-cysteine in Gaucher disease. Mol Genet Metab 129:S84. https://doi.org/10.1016/j.ymgme.2019.11.207

    Article  Google Scholar 

  233. Matalonga L, Arias A, Coll MJ, Garcia-Villoria J, Gort L, Ribes A (2014) Treatment effect of coenzyme Q(10) and an antioxidant cocktail in fibroblasts of patients with Sanfilippo disease. J Inherit Metab Dis 37:439–446. https://doi.org/10.1007/s10545-013-9668-1

    Article  CAS  PubMed  Google Scholar 

  234. Greenberg S, Frishman WH (1990) Co-enzyme Q10: a new drug for cardiovascular disease. J Clin Pharmacol 30:596–608. https://doi.org/10.1002/j.1552-4604.1990.tb01862.x

    Article  CAS  PubMed  Google Scholar 

  235. de la Mata M, Cotán D, Oropesa-Ávila M, Garrido-Maraver J, Cordero MD, Villanueva Paz M, Delgado Pavón A, Alcocer-Gómez E, de Lavera I, Ybot-González P et al (2015) Pharmacological chaperones and coenzyme Q10 treatment improves mutant β-glucocerebrosidase activity and mitochondrial function in neuronopathic forms of Gaucher disease. Sci Rep 5:10903. https://doi.org/10.1038/srep10903

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. de la Mata M, Cotán D, Oropesa-Ávila M, Villanueva-Paz M, de Lavera I, Álvarez-Córdoba M, Luzón-Hidalgo R, Suárez-Rivero JM, Tiscornia G, Sánchez-Alcázar JA (2017) Coenzyme Q10 partially restores pathological alterations in a macrophage model of Gaucher disease. Orphanet J Rare Dis 12:23. https://doi.org/10.1186/s13023-017-0574-8

    Article  PubMed  PubMed Central  Google Scholar 

  237. Corbau R, Miranda CJ, Comper F, Kalcheva P, Chisari E, Cocita C, Correia S, Pandya J, Liou B, Northcott N et al (2021) FLT201: an AAV-mediated gene therapy for type 1 Gaucher disease designed to target difficult to reach tissues world symposium 2021

Download references

Acknowledgements

Authors would like to acknowledge the academic fellowship grant from Sanofi-Genzyme. We also thank Dr. Marcia Terluk for the careful review of the manuscript.

Funding

JR is supported by Sanofi-Genzyme academic fellowship grant. RVK has received grants from NIH, Sanofi-Genzyme, and Pfizer Inc. NJW has received grants from Sanofi-Genzyme and Takeda-Shire and personal fees from Sanofi-Genzyme, Takeda-Shire, and Pfizer Inc.

Author information

Authors and Affiliations

  1. Center for Orphan Drug Research, Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, 55455, USA

    Jaehyeok Roh & Reena V. Kartha

  2. Department of Surgery, School of Medicine, University of Minnesota, Minneapolis, MN, 55455, USA

    Subbaya Subramanian

  3. Department of Human Genetics and Medicine (Hematology), Leonard Miller School of Medicine of University of Miami, Miami, FL, USA

    Neal J. Weinreb

Authors
  1. Jaehyeok Roh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Subbaya Subramanian
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Neal J. Weinreb
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Reena V. Kartha
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JR performed the literature research and drafted the manuscript; SS, NJW, and RVK participated in modifying the article.

Corresponding author

Correspondence to Reena V. Kartha.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

All authors read and approved the final manuscript.

Conflict of interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Roh, J., Subramanian, S., Weinreb, N.J. et al. Gaucher disease – more than just a rare lipid storage disease. J Mol Med 100, 499–518 (2022). https://doi.org/10.1007/s00109-021-02174-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-021-02174-z

Keywords

Search

Navigation