{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T10:09:28Z","timestamp":1789034968400,"version":"build-2803163510"},"reference-count":203,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:00Z","timestamp":1788998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>Aging is the major risk factor for synucleinopathies, including Parkinson\u2019s disease, dementia with Lewy bodies, and multiple system atrophy. However, the molecular mechanisms linking aging to. \u03b1-Synuclein cytotoxicity remain incompletely understood. The progressive decline of proteostasis is central among these mechanisms, as the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway fail to maintain the turnover of aggregation-prone proteins. In this review, we focus on the bidirectional crosstalk between \u03b1-Synuclein and the proteasome as a key driver of proteostasis collapse in synucleinopathies. Proteasome activity declines during aging, and proteasomal dysfunction is closely associated with disease progression. We first discuss how. \u03b1-Synuclein structure and posttranslational modifications determine whether the protein is targeted for degradation by the UPS or autophagy or instead acts as a proteolytic inhibitor. Next, the mechanisms by which pathogenic \u03b1-synuclein species interact with and impair 20S\/26S proteasomes, affecting proteolytic activity, subunit composition, and complex assembly, are discussed. These interactions establish a self-amplifying cycle of proteasome inhibition and \u03b1-Synuclein accumulation. As a consequence, the cellular capacity to clear misfolded proteins progressively declines, promoting toxic \u03b1-Synuclein aggregation and neurodegeneration. We further discuss the importance of autophagy on \u03b1-Synuclein turnover and how this is impaired in synucleinopathies. Finally, we highlight emerging therapeutic strategies aimed at restoring proteasome function and proteostasis. A deeper understanding of how \u03b1-Synuclein-proteasome interactions change during ageing may reveal new molecular targets and support the development of disease-modifying therapies for synucleinopathies.<\/jats:p>","DOI":"10.3389\/fcell.2026.1906331","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T09:27:16Z","timestamp":1789032436000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Breaking the proteasome balance: \u03b1-synuclein and the ubiquitin-proteasome system"],"prefix":"10.3389","volume":"14","author":[{"given":"Tariq T.","family":"Ali","sequence":"first","affiliation":[{"name":"Department of Molecular Microbiology and Genetics, Institute of Microbiology and Genetics, University of G\u00f6ttingen","place":["G\u00f6ttingen, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blagovesta","family":"Popova","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Genetics, Institute of Microbiology and Genetics, University of G\u00f6ttingen","place":["G\u00f6ttingen, Germany"]},{"name":"Department of Genetics of Eukaryotic Microorganisms, Institute of Microbiology and Genetics, University of G\u00f6ttingen","place":["G\u00f6ttingen, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerhard H.","family":"Braus","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Genetics, Institute of Microbiology and Genetics, University of G\u00f6ttingen","place":["G\u00f6ttingen, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1207","DOI":"10.1016\/J.CHEMBIOL.2013.09.009","article-title":"Site-specific differences in proteasome-dependent degradation of monoubiquitinated \u03b1-synuclein","volume":"20","author":"Abeywardana","year":"2013","journal-title":"Chem. and Biology"},{"key":"B2","first-page":"R1357","article-title":"Orchestration of selective autophagy by cargo receptors","volume-title":"Current Biology","author":"Adriaenssens","year":"2022"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1581","DOI":"10.3390\/BIOM10111581","article-title":"The proteasome activators Blm10\/PA200 enhance the proteasomal degradation of N-Terminal huntingtin","volume":"10","author":"Aladdin","year":"2020","journal-title":"Biomolecules"},{"key":"B4","doi-asserted-by":"publisher","first-page":"e70566","DOI":"10.1111\/acel.70566","article-title":"Blm10\/PA200-activated 20S proteasomes promote \u03b1-synuclein degradation and bypass proteasome inhibition in Parkinson\u2019s disease models","volume":"25","author":"Ali","year":"2026","journal-title":"Aging Cell"},{"key":"B5","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1016\/j.bbamcr.2013.11.018","article-title":"Mechanism of cleavage of alpha-synuclein by the 20S proteasome and modulation of its degradation by the RedOx state of the N-terminal methionines","volume":"1843","author":"Alvarez-Castelao","year":"2014","journal-title":"Biochimica Biophysica Acta - Mol. 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