{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T07:33:00Z","timestamp":1782977580277,"version":"3.54.5"},"reference-count":31,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,4,6]],"date-time":"2025-04-06T00:00:00Z","timestamp":1743897600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Sidransky syndrome represents a distinct variant of Parkinson\u2019s disease (PD) that is linked to pathogenic variants in the glucocerebrosidase (GBA1) gene. This disorder exhibits an earlier onset, a more severe course, and a higher dementia prevalence compared to idiopathic PD. While the pathogenesis remains debated between loss-of-function and gain-of-function mechanisms, targeted therapies are emerging. Pharmacological chaperones (PCs), like high-dose Ambroxol, aim to mitigate enzyme misfolding\u2014a primary driver of this disorder\u2014rather than addressing metabolic deficiencies seen in Gaucher disease. Despite failed trials of substrate reduction therapies, current clinical trials with Ambroxol and other PCs highlight promising avenues for disease modification. This commentary advocates for increased awareness of Sidransky syndrome to advance diagnostic strategies, promote genetic testing, and refine targeted treatments, with the potential to transform care for GBA1-related PD and prodromal stages of the disease.<\/jats:p>","DOI":"10.3390\/ijms26073435","type":"journal-article","created":{"date-parts":[[2025,4,7]],"date-time":"2025-04-07T11:24:39Z","timestamp":1744025079000},"page":"3435","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Sidransky Syndrome\u2014GBA1-Related Parkinson\u2019s Disease and Its Targeted Therapies"],"prefix":"10.3390","volume":"26","author":[{"given":"Majdolen","family":"Istaiti","sequence":"first","affiliation":[{"name":"Agyany Pharma Ltd., Jerusalem 9695614, Israel"},{"name":"Gaucher Unit, The Eisenberg R&D Authority, Shaare Zedek Medical Center, Jerusalem 9103102, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilad","family":"Yahalom","sequence":"additional","affiliation":[{"name":"Department of Neurology and Movement Disorders Unit, Shaare Zedek Medical Center, Jerusalem 9103102, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0267-2658","authenticated-orcid":false,"given":"Mikhal","family":"Cohen","sequence":"additional","affiliation":[{"name":"Department of Neurology and Movement Disorders Unit, Shaare Zedek Medical Center, Jerusalem 9103102, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Volha","family":"Skrahina","sequence":"additional","affiliation":[{"name":"Agyany Pharma Ltd., Jerusalem 9695614, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aliaksandr","family":"Skrahin","sequence":"additional","affiliation":[{"name":"Agyany Pharma Ltd., Jerusalem 9695614, Israel"},{"name":"Rare Disease Consulting RCV GmbH, Leibnizstrasse 58, 10629 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8061-5798","authenticated-orcid":false,"given":"Jan","family":"Lukas","sequence":"additional","affiliation":[{"name":"Translational Neurodegeneration Section Albrecht Kossel, Department of Neurology, University Medical Center Rostock, 18147 Rostock, Germany"},{"name":"Center for Transdisciplinary Neurosciences Rostock (CTNR), University Medical Center Rostock, University of Rostock, 18147 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arndt","family":"Rolfs","sequence":"additional","affiliation":[{"name":"Agyany Pharma Ltd., Jerusalem 9695614, Israel"},{"name":"Rare Disease Consulting RCV GmbH, Leibnizstrasse 58, 10629 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0077-8608","authenticated-orcid":false,"given":"Ari","family":"Zimran","sequence":"additional","affiliation":[{"name":"Agyany Pharma Ltd., Jerusalem 9695614, Israel"},{"name":"Gaucher Unit, The Eisenberg R&D Authority, Shaare Zedek Medical Center, Jerusalem 9103102, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1093\/qjmed\/89.9.691","article-title":"Occurrence of Parkinson\u2019s syndrome in type I Gaucher disease","volume":"89","author":"Neudorfer","year":"1996","journal-title":"QJM"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.1056\/NEJMoa0901281","article-title":"Multicenter analysis of glucocerebrosidase mutations in Parkinson\u2019s disease","volume":"361","author":"Sidransky","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Skrahin, A., Horowitz, M., Istaiti, M., Skrahina, V., Lukas, J., Yahalom, G., Cohen, M.E., Revel-Vilk, S., Goker-Alpan, O., and Becker-Cohen, M. (2024). GBA1-Associated Parkinson\u2019s Disease Is a Distinct Entity. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25137102"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"114402","DOI":"10.1016\/j.addr.2022.114402","article-title":"Lysosomal functions and dysfunctions: Molecular and cellular mechanisms underlying Gaucher disease and its association with Parkinson disease","volume":"187","author":"Horowitz","year":"2022","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2699","DOI":"10.1073\/pnas.1616152114","article-title":"Glucosylceramide synthase inhibition alleviates aberrations in synucleinopathy models","volume":"114","author":"Sardi","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","first-page":"557","article-title":"Safety, Pharmacokinetics, and Pharmacodynamics of Oral Venglustat in Patients with Parkinson\u2019s Disease and a GBA Mutation: Results from Part 1 of the Randomized, Double-Blinded, Placebo-Controlled MOVES-PD Trial","volume":"12","author":"Peterschmitt","year":"2022","journal-title":"J. Park. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1016\/S1474-4422(23)00205-3","article-title":"Safety and efficacy of venglustat in GBA1-associated Parkinson\u2019s disease: An international, multicentre, double-blind, randomised, placebo-controlled, phase 2 trial","volume":"22","author":"Giladi","year":"2023","journal-title":"Lancet Neurol."},{"key":"ref_8","first-page":"2712","article-title":"The contribution of mutant GBA to the development of Parkinson disease in Drosophila","volume":"25","author":"Maor","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"31380","DOI":"10.1038\/srep31380","article-title":"Parkinson disease-linked GBA mutation effects reversed by molecular chaperones in human cell and fly models","volume":"6","author":"Beavan","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1001\/jamaneurol.2019.4611","article-title":"Ambroxol for the Treatment of Patients With Parkinson Disease With and Without Glucocerebrosidase Gene Mutations: A Nonrandomized, Noncontrolled Trial","volume":"77","author":"Mullin","year":"2020","journal-title":"JAMA Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Silveira, C.R.A., MacKinley, J., Coleman, K., Li, Z., Finger, E., Bartha, R., Morrow, S.A., Wells, J., Borrie, M., and Tirona, R.G. (2019). Ambroxol as a novel disease-modifying treatment for Parkinson\u2019s disease dementia: Protocol for a single-centre, randomized, double-blind, placebo-controlled trial. BMC Neurol., 19.","DOI":"10.1186\/s12883-019-1252-3"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1002\/mds.27903","article-title":"Substrate reduction therapy for GBA1-associated Parkinsonism: Are we betting on the wrong mouse?","volume":"35","author":"Sidransky","year":"2020","journal-title":"Mov. Disord."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1482","DOI":"10.1093\/hmg\/ddp061","article-title":"No evidence for activation of the unfolded protein response in neuronopathic models of Gaucher disease","volume":"18","author":"Vitner","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Polinski, N.K., Martinez, T.N., Gorodinsky, A., Gareus, R., Sasner, M., Herberth, M., Switzer, R., Ahmad, S.O., Cosden, M., and Kandebo, M. (2021). Decreased glucocerebrosidase activity and substrate accumulation of glycosphingolipids in a novel GBA1 D409V knock-in mouse model. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0252325"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/ana.23614","article-title":"Glucocerebrosidase deficiency in substantia nigra of parkinson disease brains","volume":"72","author":"Gegg","year":"2012","journal-title":"Ann. Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1111\/j.1471-4159.2012.07879.x","article-title":"Glucocerebrosidase mutations alter the endoplasmic reticulum and lysosomes in Lewy body disease","volume":"123","author":"Hanson","year":"2012","journal-title":"J. Neurochem."},{"key":"ref_17","first-page":"S183","article-title":"Gene Therapy for Parkinson\u2019s Disease Associated with GBA1 Mutations","volume":"11","author":"Abeliovich","year":"2021","journal-title":"J. Park. Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2134","DOI":"10.1002\/mds.29190","article-title":"Putaminal Recombinant Glucocerebrosidase Delivery with Magnetic Resonance-Guided Focused Ultrasound in Parkinson\u2019s Disease: A Phase I Study","volume":"37","author":"Meng","year":"2022","journal-title":"Mov. Disord."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1002\/mds.29346","article-title":"A Phase 1B Trial in GBA1-Associated Parkinson\u2019s Disease of BIA-28-6156, a Glucocerebrosidase Activator","volume":"38","author":"Kruithof","year":"2023","journal-title":"Mov. Disord."},{"key":"ref_20","first-page":"899","article-title":"Parkinson\u2019s Disease Drug Therapies in the Clinical Trial Pipeline: 2024 Update","volume":"14","author":"McFarthing","year":"2024","journal-title":"J. Park. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1517\/17460441.2011.629646","article-title":"Ambroxol: A multifaceted molecule with additional therapeutic potentials in respiratory disorders of childhood","volume":"6","author":"Paleari","year":"2011","journal-title":"Expert. Opin. Drug Discov."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"23502","DOI":"10.1074\/jbc.M109.012393","article-title":"Identification and characterization of ambroxol as an enzyme enhancement agent for Gaucher disease","volume":"284","author":"Maegawa","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.bcmd.2012.09.006","article-title":"Pilot study using ambroxol as a pharmacological chaperone in type 1 Gaucher disease","volume":"50","author":"Zimran","year":"2013","journal-title":"Blood Cells Mol. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1002\/acn3.292","article-title":"Ambroxol chaperone therapy for neuronopathic Gaucher disease: A pilot study","volume":"3","author":"Narita","year":"2016","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1111\/jphp.13273","article-title":"Drug repositioning: A brief overview","volume":"72","author":"Jourdan","year":"2020","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1007\/978-1-4939-8955-3_5","article-title":"Transcriptomic Data Mining and Repurposing for Computational Drug Discovery","volume":"1903","author":"Wang","year":"2019","journal-title":"Methods Mol. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1002\/ajh.26131","article-title":"Upgrading the evidence for the use of ambroxol in Gaucher disease and GBA related Parkinson: Investigator initiated registry based on real life data","volume":"96","author":"Istaiti","year":"2021","journal-title":"Am. J. Hematol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.bcmd.2012.10.007","article-title":"Ambroxol as a pharmacological chaperone for mutant glucocerebrosidase","volume":"50","author":"Maor","year":"2013","journal-title":"Blood Cells Mol. Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1056\/NEJMra2401857","article-title":"Parkinson\u2019s Disease","volume":"391","author":"Tanner","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2652","DOI":"10.1093\/brain\/awae188","article-title":"Relevance of genetic testing in the gene-targeted trial era: The Rostock Parkinson\u2019s disease study","volume":"147","author":"Westenberger","year":"2024","journal-title":"Brain"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/s41531-018-0058-0","article-title":"Prevalence of Parkinson\u2019s disease across North America","volume":"4","author":"Marras","year":"2018","journal-title":"Npj Park. Dis."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/7\/3435\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:11:10Z","timestamp":1760029870000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/7\/3435"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,6]]},"references-count":31,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["ijms26073435"],"URL":"https:\/\/doi.org\/10.3390\/ijms26073435","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,6]]}}}