{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T02:16:21Z","timestamp":1788401781934,"version":"build-2803163510"},"reference-count":50,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T00:00:00Z","timestamp":1755648000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Rappaport Family Institute for Research in the Medical Sciences"},{"name":"Allen and Jewel Prince Center for Neurodegenerative Disorders of the Brain"},{"name":"Technion Research"},{"name":"Reta Lila Weston Institute"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Parkinson\u2019s disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra and the presence of \u03b1-synuclein-positive inclusions known as Lewy bodies. Synphilin-1 is a protein of unknown function that interacts with \u03b1-synuclein and has been shown to exhibit cytoprotective effects in both in vitro and in vivo models. In this study, we investigated whether synphilin-1 is phosphorylated by pathological CDK5 and explored the consequences of this modification. Pathological activation of CDK5 occurs mainly through its association with the calpain-cleaved protein p25. Although CDK5 inhibition protects against neurodegeneration in pharmacological PD models, we now show that p25 levels are increased in PD brains. Furthermore, we demonstrate that CDK5, in conjunction with p25, directly phosphorylates synphilin-1, mainly at serine 566. This phosphorylation reduces synphilin-1\u2032s interaction with SIAH1, leading to reduced ubiquitination and subsequent accumulation. We also observed that CDK5-phosphorylated synphilin-1 exhibits a reduced ability to interact with PINK1 and to promote basal levels of mitophagy. Consistent with these findings, the phosphorylation-mimicking synphilin-1 S566E shows decreased translocation to mitochondria, and synphilin-1 levels are reduced in the mitochondria of PD brains compared to age-matched controls. Finally, synphilin-1 S566E promotes retraction of neuronal processes. Taken together, our results suggest that phosphorylation by CDK5 disrupts synphilin-1\u2032s interactions with its protein partners, rendering it more toxic and impairing its ability to support mitophagy and maintain neuronal process homeostasis. We hypothesize that phosphorylation of synphilin-1 by CDK5 may contribute to the pathogenesis of PD.<\/jats:p>","DOI":"10.3390\/ijms26168048","type":"journal-article","created":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T08:02:44Z","timestamp":1755763364000},"page":"8048","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["CDK5 Inhibits Synphilin-1 Ubiquitination and Basal Mitophagy: Implications for Parkinson\u2019s Disease"],"prefix":"10.3390","volume":"26","author":[{"given":"Mor","family":"Savyon","sequence":"first","affiliation":[{"name":"Department of Biochemistry, The B. Rappaport Faculty of Medicine and Institute of Medical Research, Technion-Israel Institute of Technology, Haifa 31096, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eyal","family":"Avraham","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, The B. Rappaport Faculty of Medicine and Institute of Medical Research, Technion-Israel Institute of Technology, Haifa 31096, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5176-5608","authenticated-orcid":false,"given":"Ankit Kumar","family":"Shah","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, The B. Rappaport Faculty of Medicine and Institute of Medical Research, Technion-Israel Institute of Technology, Haifa 31096, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haya","family":"Hamza","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, The B. Rappaport Faculty of Medicine and Institute of Medical Research, Technion-Israel Institute of Technology, Haifa 31096, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymonde","family":"Szargel","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, The B. Rappaport Faculty of Medicine and Institute of Medical Research, Technion-Israel Institute of Technology, Haifa 31096, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatimah","family":"Abd Elghani","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, The B. Rappaport Faculty of Medicine and Institute of Medical Research, Technion-Israel Institute of Technology, Haifa 31096, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malik","family":"Farhoud","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, The B. Rappaport Faculty of Medicine and Institute of Medical Research, 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 B. Rappaport Faculty of Medicine and Institute of Medical Research, Technion-Israel Institute of Technology, Haifa 31096, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Pavoncello","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, The B. Rappaport Faculty of Medicine and Institute of Medical Research, Technion-Israel Institute of Technology, Haifa 31096, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8451-3927","authenticated-orcid":false,"given":"Sofia","family":"Zaer","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, The B. Rappaport Faculty of Medicine and Institute of Medical Research, Technion-Israel Institute of Technology, Haifa 31096, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3502-8815","authenticated-orcid":false,"given":"Rina","family":"Bandopadhyay","sequence":"additional","affiliation":[{"name":"Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, 1 Wakefield Street, London WC1N 1PJ, UK"}],"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 B. 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Rappaport Faculty of Medicine and Institute of Medical Research, Technion-Israel Institute of Technology, Haifa 31096, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1038\/42166","article-title":"Alpha-synuclein in Lewy bodies","volume":"388","author":"Spillantini","year":"1997","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1318","DOI":"10.1038\/3311","article-title":"Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to early-onset Parkinson disease","volume":"4","author":"Conway","year":"1998","journal-title":"Nat. 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