{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T20:29:24Z","timestamp":1771100964315,"version":"3.50.1"},"reference-count":147,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,10,19]],"date-time":"2022-10-19T00:00:00Z","timestamp":1666137600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["WE 6585\/1-1, NG 101\/6-1"],"award-info":[{"award-number":["WE 6585\/1-1, NG 101\/6-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:p>Among posttranslational modifications, directed proteolytic processes have the strongest impact on protein integrity. They are executed by a variety of cellular machineries and lead to a wide range of molecular consequences. Compared to other forms of proteolytic enzymes, the class of calcium-activated calpains is considered as modulator proteases due to their limited proteolytic activity, which changes the structure and function of their target substrates. In the context of neurodegeneration and - in particular - polyglutamine disorders, proteolytic events have been linked to modulatory effects on the molecular pathogenesis by generating harmful breakdown products of disease proteins. These findings led to the formulation of the <jats:italic>toxic fragment hypothesis<\/jats:italic>, and calpains appeared to be one of the key players and auspicious therapeutic targets in Huntington disease and Machado Joseph disease. This review provides a current survey of the role of calpains in proteolytic processes found in polyglutamine disorders. Together with insights into general concepts behind <jats:italic>toxic fragments<\/jats:italic> and findings in polyglutamine disorders, this work aims to inspire researchers to broaden and deepen the knowledge in this field, which will help to evaluate calpain-mediated proteolysis as a unifying and therapeutically targetable posttranslational mechanism in neurodegeneration.<\/jats:p>","DOI":"10.3389\/fnmol.2022.1020104","type":"journal-article","created":{"date-parts":[[2022,10,19]],"date-time":"2022-10-19T05:00:37Z","timestamp":1666155637000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Calpain-mediated proteolysis as driver and modulator of polyglutamine toxicity"],"prefix":"10.3389","volume":"15","author":[{"given":"Rana Dilara","family":"Incebacak Eltemur","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huu Phuc","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonasz Jeremiasz","family":"Weber","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,10,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"4474","DOI":"10.1128\/MCB.20.12.4474-4481.2000","article-title":"Disruption of the murine calpain small subunit gene, Capn4: calpain is essential for embryonic development but not for cell growth and division","volume":"20","author":"Arthur","year":"2000","journal-title":"Mol. 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