{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T01:48:31Z","timestamp":1760233711001,"version":"build-2065373602"},"reference-count":56,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2021,2,15]],"date-time":"2021-02-15T00:00:00Z","timestamp":1613347200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Gaucher disease (GD), the most common lysosomal storage disorder (LSD), is caused by autosomal recessive mutations of the glucocerebrosidase gene, GBA1. In the majority of cases, GD has a non-neuropathic chronic form with adult onset (GD1), while other cases are more acute and severer neuropathic forms with early onset (GD2\/3). Currently, no radical therapies are established for GD2\/3. Notably, GD1, but not GD2\/3, is associated with increased risk of Parkinson\u2019s disease (PD), the elucidation of which might provide a clue for novel therapeutic strategies. In this context, the objective of the present study is to discuss that the evolvability of \u03b1-synuclein (\u03b1S) might be differentially involved in GD subtypes. Hypothetically, aging-associated PD features with accumulation of \u03b1S, and the autophagy-lysosomal dysfunction might be an antagonistic pleiotropy phenomenon derived from \u03b1S evolvability in the development in GD1, without which neuropathies like GD2\/3 might be manifested due to the autophagy-lysosomal dysfunction. Supposing that the increased severity of GD2\/3 might be attributed to the decreased activity of \u03b1S evolvability, suppressing the expression of \u03b2-synuclein (\u03b2S), a potential buffer against \u03b1S evolvability, might be therapeutically efficient. Of interest, a similar view might be applicable to Niemann-Pick type C (NPC), another LSD, given that the adult type of NPC, which is comorbid with Alzheimer\u2019s disease, exhibits milder medical symptoms compared with those of infantile NPC. Thus, it is predicted that the evolvability of amyloid \u03b2 and tau, might be beneficial for the adult type of NPC. Collectively, a better understanding of amyloidogenic evolvability in the pathogenesis of LSD may inform rational therapy development.<\/jats:p>","DOI":"10.3390\/biom11020289","type":"journal-article","created":{"date-parts":[[2021,2,15]],"date-time":"2021-02-15T22:58:01Z","timestamp":1613429881000},"page":"289","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Therapeutic Potential of \u03b1S Evolvability for Neuropathic Gaucher Disease"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3560-3392","authenticated-orcid":false,"given":"Jianshe","family":"Wei","sequence":"first","affiliation":[{"name":"Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-0057, Japan"},{"name":"Institute for Brain Sciences Research, School of Life Sciences, Henan University, Kaifeng 475004, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshiki","family":"Takamatsu","sequence":"additional","affiliation":[{"name":"Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-0057, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryoko","family":"Wada","sequence":"additional","affiliation":[{"name":"Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-0057, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masayo","family":"Fujita","sequence":"additional","affiliation":[{"name":"Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-0057, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gilbert","family":"Ho","sequence":"additional","affiliation":[{"name":"PCND Neuroscience Research Institute, Poway, CA 92064, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eliezer","family":"Masliah","sequence":"additional","affiliation":[{"name":"Division of Neurosciences, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4626-950X","authenticated-orcid":false,"given":"Makoto","family":"Hashimoto","sequence":"additional","affiliation":[{"name":"Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-0057, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,15]]},"reference":[{"key":"ref_1","first-page":"1","article-title":"Lysosomal storage diseases","volume":"2","author":"Ferreira","year":"2017","journal-title":"Transl. 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