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Barchas, MD, DLFAPA Professor in Translational Psychiatry"},{"name":"The Morley-Mather Chair in Neuropsychiatry at University Hospitals Cleveland Medical Center","id":[{"id":"https:\/\/ror.org\/01gc0wp38","id-type":"ROR","asserted-by":"crossref"}]},{"name":"The Howard T. Karsner Endowed Professorship at CWRU"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Acta Neuropathol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Mutations in coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2), including the Parkinson\u2019s disease (PD)-linked CHCHD2\n                    <jats:sup>T61I<\/jats:sup>\n                    mutation, are associated with Lewy body disorders (LBDs) by unknown mechanisms. Here, we demonstrate that CHCHD2\n                    <jats:sup>T61I<\/jats:sup>\n                    exacerbates age-related brain pathologies, including axonal degeneration and cognitive deficits, by disrupting the mitochondria-lysosome axis. Specifically, CHCHD2\n                    <jats:sup>T61I<\/jats:sup>\n                    binds and reduces cathepsin B (CTSB) and cathepsin L (CTSL) levels, inducing lysosomal membrane permeability and impairing \u03b1-synuclein fibril clearance. We also demonstrate that human CHCHD2 declines in the brain with age, while expression of wild-type CHCHD2 safeguards against age-related neuroinflammation, dopaminergic neuron loss, insoluble protein aggregation, and structural deterioration of mitochondria and lysosomes. These findings, supported by observed reductions in CTSB and CHCHD2 in human LBD brains, establish CHCHD2 as a key regulator of neuronal resilience to aging and proteostatic collapse via the mitochondria-lysosome axis. Preventing age-associated CHCHD2 decline offers a therapeutic strategy to preserve brain health throughout aging.\n                  <\/jats:p>","DOI":"10.1007\/s00401-026-03093-4","type":"journal-article","created":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T20:05:46Z","timestamp":1791921946000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CHCHD2 mitigates age-associated proteostatic collapse by maintaining homeostasis of the mitochondria-lysosome axis"],"prefix":"10.1007","volume":"152","author":[{"given":"Teresa R.","family":"Kee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brianna M.","family":"Masters","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khoi D.","family":"Tran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna","family":"Jeon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ma","family":"Long","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophia A.","family":"Khan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edwin","family":"V\u00e1zquez-Rosa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Preethy S.","family":"Sridharan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeojung","family":"Koh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisashi","family":"Fujioka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dale","family":"Chaput","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinming","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingyu","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew A.","family":"Pieper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David E.","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jung-A A.","family":"Woo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,13]]},"reference":[{"key":"3093_CR1","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1007\/978-1-4939-8873-0_21","volume":"1880","author":"S Aits","year":"2019","unstructured":"Aits S (2019) Methods to detect loss of lysosomal membrane integrity. 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