{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T05:56:53Z","timestamp":1780639013046,"version":"3.54.1"},"reference-count":54,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T00:00:00Z","timestamp":1776124800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Parkinson\u2019s disease (PD) is a common neurodegenerative disorder marked by progressive loss of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of Lewy bodies, intracellular inclusions enriched in \u03b1-synuclein. Synphilin-1 interacts with \u03b1-synuclein, localizes to Lewy bodies, and has been implicated in inclusion formation and neuroprotection in cellular and animal models; however, its physiological function in vivo remains poorly defined. Here, we generated and characterized a synphilin-1 knockout (Sph-1 KO) mouse by targeted genetic deletion of the Sph-1 locus and performed a comprehensive phenotyping battery including behavioral testing as well as biochemical, histological, structural, and ultrastructural analyses. Sph-1 KO mice survived to nearly two years of age and showed normal body weight, lifespan, motor performance, learning and memory, anxiety-like behavior, attention, and gross brain morphology. Western blot analyses indicated that levels of \u03b1-synuclein and synaptic proteins were largely unchanged. While outer mitochondrial membrane proteins were unaffected, the mitochondrial matrix protein HSP60 was reduced, consistent with altered mitochondrial proteostasis in the absence of synphilin-1. Strikingly, histochemical analyses, magnetic resonance imaging, and electron microscopy revealed early-onset hydrocephalus in Sph-1 KO mice associated with severe loss and disorganization of motile ependymal cilia in the ventricular lining, a cell type that normally expresses high levels of synphilin-1. Ultrastructural and immunohistochemical analyses revealed disrupted ependymal architecture, mislocalization of acetylated \u03b1-tubulin to the cytoplasm, cellular swelling, and enlarged, aberrant mitochondria, whereas cortical neurons appeared largely structurally unaffected. Together, these findings identify synphilin-1 as a key regulator of microtubule organization and cytoskeletal\/organelle homeostasis in ependymal cells, required to maintain motile ciliogenesis, cerebrospinal fluid flow, and ventricular integrity. This unexpected role for synphilin-1 in ciliated brain epithelia, along with a reduction in the critical mitochondrial chaperone HSP60, broadens our understanding of synphilin-1 biology and provides a new framework for its potential relevance to PD-associated pathology.<\/jats:p>","DOI":"10.3390\/ijms27083499","type":"journal-article","created":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T12:23:56Z","timestamp":1776169436000},"page":"3499","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Synphilin-1 Is Essential for Cytoskeletal Integrity of Brain Ventricular Cilia and Mitochondrial Proteostasis"],"prefix":"10.3390","volume":"27","author":[{"given":"Malik","family":"Farhoud","sequence":"first","affiliation":[{"name":"Department of Biochemistry, The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, 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Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatimah","family":"Abd Elghani","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vered","family":"Shani","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Toren-Hershkoviz","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia","family":"Zaer","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Galit","family":"Saar","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihi","family":"Shaulov","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zagorka","family":"Vitic","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cell Biology, School of Brain Sciences and Cognition, Faculty of Medicine, Ben-Gurion University of Negev, Be\u2019er-Sheva 84105, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2312-9531","authenticated-orcid":false,"given":"Claude","family":"Brodski","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cell Biology, School of Brain Sciences and Cognition, Faculty of Medicine, Ben-Gurion University of Negev, Be\u2019er-Sheva 84105, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5141-3858","authenticated-orcid":false,"given":"Inon","family":"Maoz","sequence":"additional","affiliation":[{"name":"Department of Occupational Therapy, Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa 3498838, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salman","family":"Zubedat","sequence":"additional","affiliation":[{"name":"Department of Occupational Therapy, Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa 3498838, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avi","family":"Avital","sequence":"additional","affiliation":[{"name":"Department of Occupational Therapy, Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa 3498838, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3832-3211","authenticated-orcid":false,"given":"Hazem","family":"Safory","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Engelender","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/S0140-6736(23)01478-2","article-title":"The pathogenesis of Parkinson\u2019s disease","volume":"403","author":"Morris","year":"2024","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e202012095","DOI":"10.1083\/jcb.202012095","article-title":"The cell biology of Parkinson\u2019s disease","volume":"220","author":"Panicker","year":"2021","journal-title":"J. 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