{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T03:48:32Z","timestamp":1790999312156,"version":"4.1.0"},"reference-count":73,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,5,12]],"date-time":"2023-05-12T00:00:00Z","timestamp":1683849600000},"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. Mol. Neurosci."],"abstract":"<jats:p>The involvement of mitochondrial dysfunction in cystatin B (CSTB) deficiency has been suggested, but its role in the onset of neurodegeneration, myoclonus, and ataxia in the CSTB-deficient mouse model (<jats:italic>Cstb<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic>) is yet unknown. CSTB is an inhibitor of lysosomal and nuclear cysteine cathepsins. In humans, partial loss-of-function mutations cause the progressive myoclonus epilepsy neurodegenerative disorder, EPM1. Here we applied proteome analysis and respirometry on cerebellar synaptosomes from early symptomatic (<jats:italic>Cstb<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic>) mice to identify the molecular mechanisms involved in the onset of CSTB-deficiency associated neural pathogenesis. Proteome analysis showed that CSTB deficiency is associated with differential expression of mitochondrial and synaptic proteins, and respirometry revealed a progressive impairment in mitochondrial function coinciding with the onset of myoclonus and neurodegeneration in (<jats:italic>Cstb<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic>) mice. This mitochondrial dysfunction was not associated with alterations in mitochondrial DNA copy number or membrane ultrastructure. Collectively, our results show that CSTB deficiency generates a defect in synaptic mitochondrial bioenergetics that coincides with the onset and progression of the clinical phenotypes, and thus is likely a contributor to the pathogenesis of EPM1.<\/jats:p>","DOI":"10.3389\/fnmol.2023.1175851","type":"journal-article","created":{"date-parts":[[2023,5,12]],"date-time":"2023-05-12T05:27:35Z","timestamp":1683869255000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Progressive mitochondrial dysfunction in cerebellar synaptosomes of cystatin B-deficient mice"],"prefix":"10.3389","volume":"16","author":[{"given":"Katarin","family":"Gorski","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher B.","family":"Jackson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuula A.","family":"Nyman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronika","family":"Rezov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brendan J.","family":"Battersby","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna-Elina","family":"Lehesjoki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,5,12]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1038\/sj.ejhg.5201300","article-title":"Loss of lysosomal association of cystatin B proteins representing progressive myoclonus epilepsy, EPM1, mutations","volume":"13","author":"Alakurtti","year":"2005","journal-title":"Eur. 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