{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T15:14:13Z","timestamp":1786115653313,"version":"build-2736575974"},"reference-count":94,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"crossref","award":["P2022JKTWH"],"award-info":[{"award-number":["P2022JKTWH"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"crossref"}]},{"award":["P2022JKTWH"],"award-info":[{"award-number":["P2022JKTWH"]}],"id":[{"id":"https:\/\/ror.org\/019w4f821","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Fondazione Telethon-Italy","award":["GMR25T1094"],"award-info":[{"award-number":["GMR25T1094"]}]},{"award":["GMR25T1094"],"award-info":[{"award-number":["GMR25T1094"]}],"id":[{"id":"https:\/\/ror.org\/04xraxn18","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100002108","name":"Friedreich\u2019s Ataxia Research Alliance","doi-asserted-by":"crossref","award":["821396 [RG]"],"award-info":[{"award-number":["821396 [RG]"]}],"id":[{"id":"10.13039\/100002108","id-type":"DOI","asserted-by":"crossref"}]},{"award":["821396 [RG]"],"award-info":[{"award-number":["821396 [RG]"]}],"id":[{"id":"https:\/\/ror.org\/04edgdk70","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Repeat expansion cerebellar ataxias comprise a genetically and mechanistically heterogeneous group of neurodegenerative disorders unified by the pathological expansion of short tandem repeats (STRs) beyond a disease-causing threshold. Depending on their genomic localization, these expansions can lead to toxic protein gain-of-function, as in polyglutamine (polyQ) cerebellar ataxias, or to RNA-mediated toxicity and repeat-associated non-AUG (RAN) translation, for which recent evidence supports a major pathogenic role in non-coding spinocerebellar ataxias (SCAs). Despite these distinct upstream mechanisms, disruption of neuronal homeostasis occurs through converging pathogenic processes, including proteostasis impairment, transcriptional dysregulation, and mitochondrial dysfunction, leading to progressive neuronal loss. Importantly, impaired autophagy has been consistently reported across multiple repeat expansion ataxias, including both dominant SCAs and recessive conditions, such as Friedreich\u2019s ataxia, suggesting that impairment of this pathway may represent a shared downstream event in disease progression. Indeed, in polyQ cerebella ataxias, the accumulation of misfolded and aggregation-prone proteins places a substantial burden on cellular quality control systems, particularly the ubiquitin-proteasome system and autophagy. Similarly, in non-coding SCAs, toxic RNA species and RAN-derived peptides might interfere with protein clearance mechanisms and contribute to cellular stress. In this review, we will discuss the evidence supporting autophagy impairment as a convergent pathogenic pathway in repeat expansion cerebellar ataxias.<\/jats:p>","DOI":"10.3390\/cells15151411","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T09:15:22Z","timestamp":1785834922000},"page":"1411","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Autophagy at the Crossroads of Protein and RNA Toxicity in Repeat Expansion Cerebellar Ataxias"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-3740-9733","authenticated-orcid":false,"given":"Silvia","family":"Tortoriello","sequence":"first","affiliation":[{"name":"Institute of Translational Pharmacology, National Research Council (CNR), 00133 Rome, Italy"},{"name":"Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5038-0767","authenticated-orcid":false,"given":"Simona","family":"Rossi","sequence":"additional","affiliation":[{"name":"Institute of Translational Pharmacology, National Research Council (CNR), 00133 Rome, Italy"},{"name":"Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7136-066X","authenticated-orcid":false,"given":"Ilaria","family":"Della Valle","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy"},{"name":"Graduate Program in Cell and Molecular Biology, Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6646-7653","authenticated-orcid":false,"given":"Nadia","family":"D\u2019Ambrosi","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0342-8961","authenticated-orcid":false,"given":"Mauro","family":"Cozzolino","sequence":"additional","affiliation":[{"name":"Institute of Translational Pharmacology, National Research Council (CNR), 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1136\/pn-2023-003938","article-title":"Repeat Expansion Disorders","volume":"25","author":"Chen","year":"2025","journal-title":"Pract. 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