{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T10:34:29Z","timestamp":1790764469857,"version":"4.1.0"},"reference-count":90,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,12,28]],"date-time":"2021-12-28T00:00:00Z","timestamp":1640649600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NS099328, NS121826"],"award-info":[{"award-number":["NS099328, NS121826"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Michael J Fox Foundation","award":["02116"],"award-info":[{"award-number":["02116"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Neuronal loss in Parkinson\u2019s disease and related brain diseases has been firmly linked to the abundant neuronal protein \u03b1-synuclein (\u03b1S). However, we have gained surprisingly little insight into how exactly \u03b1S exerts toxicity in these diseases. Hypotheses of proteotoxicity, disturbed vesicle trafficking, mitochondrial dysfunction and other toxicity mechanisms have been proposed, and it seems possible that a combination of different mechanisms may drive pathology. A toxicity mechanism that has caught increased attention in the recent years is \u03b1S-related lipotoxicity. Lipotoxicity typically occurs in a cell when fatty acids exceed the metabolic needs, triggering a flux into harmful pathways of non-oxidative metabolism. Genetic and experimental approaches have revealed a significant overlap between lipid storage disorders, most notably Gaucher\u2019s disease, and synucleinopathies. There is accumulating evidence for lipid aberrations causing synuclein misfolding as well as for \u03b1S excess and misfolding causing lipid aberration. Does that mean the key problem in synucleinopathies is lipotoxicity, the accumulation of harmful lipid species or alteration in lipid equilibrium? Here, we review the existing literature in an attempt to get closer to an answer.<\/jats:p>","DOI":"10.3390\/biom12010040","type":"journal-article","created":{"date-parts":[[2021,12,28]],"date-time":"2021-12-28T06:55:03Z","timestamp":1640674503000},"page":"40","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Lipotoxicity Downstream of \u03b1-Synuclein Imbalance: A Relevant Pathomechanism in Synucleinopathies?"],"prefix":"10.3390","volume":"12","author":[{"given":"Arati","family":"Tripathi","sequence":"first","affiliation":[{"name":"Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saranna","family":"Fanning","sequence":"additional","affiliation":[{"name":"Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6676-0107","authenticated-orcid":false,"given":"Ulf","family":"Dettmer","sequence":"additional","affiliation":[{"name":"Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1016\/S0140-6736(04)17103-1","article-title":"Alpha-Synuclein Locus Duplication as a Cause of Familial Parkinson\u2019s Disease","volume":"364","author":"Kachergus","year":"2004","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1126\/science.1090278","article-title":"Alpha-Synuclein Locus Triplication Causes Parkinson\u2019s Disease","volume":"302","author":"Singleton","year":"2003","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1001\/jama.296.6.661","article-title":"Collaborative Analysis of Alpha-Synuclein Gene Promoter Variability and Parkinson Disease","volume":"296","author":"Maraganore","year":"2006","journal-title":"JAMA"},{"key":"ref_4","first-page":"1327","article-title":"Genetic Variability in the SNCA Gene Influences Alpha-Synuclein Levels in the Blood and Brain","volume":"22","author":"Fuchs","year":"2008","journal-title":"FASEB J. 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