{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T23:49:59Z","timestamp":1787010599854,"version":"build-2736575974"},"posted":{"date-parts":[[2024,3,4]]},"group-title":"Neuroscience","reference-count":73,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,3,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  \u03b1-synuclein (\u03b1Syn) is a presynaptic and nuclear protein that aggregates in important neurodegenerative diseases such as Parkinson\u2019s Disease (PD), Parkinson\u2019s Disease Dementia (PDD) and Lewy Body Dementia (LBD). Our past work suggests that nuclear \u03b1Syn may regulate forms of DNA double-strand break (DSB) repair in HAP1 cells after DNA damage induction with the chemotherapeutic agent bleomycin\n                  <jats:sup>1<\/jats:sup>\n                  . Here, we report that genetic deletion of \u03b1Syn specifically impairs the non-homologous end-joining (NHEJ) pathway of DSB repair using an extrachromosomal plasmid-based repair assay in HAP1 cells. Importantly, induction of a single DSB at a precise genomic location using a CRISPR\/Cas9 lentiviral approach also showed the importance of \u03b1Syn in regulating NHEJ in HAP1 cells and primary mouse cortical neuron cultures. This modulation of DSB repair is dependent on the activity of the DNA damage response signaling kinase DNA-PK\n                  <jats:sub>cs<\/jats:sub>\n                  , since the effect of \u03b1Syn loss-of-function is reversed by DNA-PK\n                  <jats:sub>cs<\/jats:sub>\n                  inhibition. Using\n                  <jats:italic>in vivo<\/jats:italic>\n                  multiphoton imaging in mouse cortex after induction of \u03b1Syn pathology, we find an increase in longitudinal cell survival of inclusion-bearing neurons after Polo-like kinase (PLK) inhibition, which is associated with an increase in the amount of aggregated \u03b1Syn within inclusions. Together, these findings suggest that \u03b1Syn plays an important physiologic role in regulating DSB repair in both a transformed cell line and in primary cortical neurons. Loss of this nuclear function may contribute to the neuronal genomic instability detected in PD, PDD and DLB and points to DNA-PK\n                  <jats:sub>cs<\/jats:sub>\n                  and PLK as potential therapeutic targets.\n                <\/jats:p>","DOI":"10.1101\/2024.02.29.582819","type":"posted-content","created":{"date-parts":[[2024,3,4]],"date-time":"2024-03-04T15:40:12Z","timestamp":1709566812000},"source":"Crossref","is-referenced-by-count":1,"title":["Alpha-synuclein regulates the repair of genomic DNA double-strand breaks in a DNA-PK\n                  <sub>cs<\/sub>\n                  -dependent manner"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3999-0526","authenticated-orcid":false,"given":"Elizabeth P.","family":"Rose","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7283-697X","authenticated-orcid":false,"given":"Valerie 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