{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T12:57:13Z","timestamp":1768568233457,"version":"3.49.0"},"posted":{"date-parts":[[2025,8,15]]},"group-title":"Neurology","reference-count":70,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T00:00:00Z","timestamp":1755216000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,8,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Genome-wide association studies (GWAS) have contributed significantly to unraveling the genetic bases of complex diseases such as Parkinson\u2019s disease (PD); yet experimental evidence for causation is often elusive. Here, we hypothesized that non-manifesting carriers of a PD-causing mutation in the\n                  <jats:italic>LRRK2<\/jats:italic>\n                  gene could express genetic modifiers conferring disease protection. Using a pluripotent stem cell-based model, we showed that dopaminergic neurons derived from these individuals were partially protected from the disease in vitro, and that this protective effect is genetically driven. Whole-exome sequencing identified a previously unreported low-frequency variant in cyclin G-associated kinase (GAK) that was associated with a nearly nine-year delay in age at onset among LRRK2 mutation carriers in a local cohort, although replication in additional cohorts was inconclusive. To rule out inter-cohort heterogeneity, we used CRISPR\/Cas9-mediated gene editing to isolate the effect of the mutation. We found that the candidate protective variant prevented neuron loss in vitro along with an improvement of several indicators endocytic-mediated transport. Together, our findings provide mechanistic insights into PD pathogenesis and actionable genetic information for the prognosis of PD patients.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>One Sentence Summary<\/jats:title>\n                  <jats:p>Investigating genetic protection against Parkinson\u2019s disease in non-manifesting carriers of LRRK2 mutations by CRISPR\/Cas9-based genome edition.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.08.13.25333123","type":"posted-content","created":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T17:55:16Z","timestamp":1755280516000},"source":"Crossref","is-referenced-by-count":0,"title":["Low-frequency genetic variants in GAK enhance Golgi function and protect against Parkinson\u2019s disease"],"prefix":"10.64898","author":[{"given":"C.","family":"Calatayud","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"I.","family":"Fernandez-Carasa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"N.","family":"Spataro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C.","family":"Mussolino","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Y.","family":"Richaud-Patin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A.","family":"Faella","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4582-0702","authenticated-orcid":false,"given":"R.","family":"Fern\u00e1ndez-Santiago","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M.","family":"Ezquerra","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T.","family":"Courtin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S.","family":"Bandres-Ciga","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A.","family":"Miguez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J.M.","family":"Canals","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M.","family":"Chiritoiu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"V.","family":"Malhotra","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A.","family":"Garrido","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M.J.","family":"Marti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"E.","family":"Tolosa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"E.","family":"Bosch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7757-4630","authenticated-orcid":false,"given":"T.","family":"Cathomen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0938-4106","authenticated-orcid":false,"given":"F.H.","family":"Gage","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2189-9775","authenticated-orcid":false,"given":"A.","family":"Raya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3988-6254","authenticated-orcid":false,"given":"A.","family":"Consiglio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025081809000536000_2025.08.13.25333123v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(09)60492-X"},{"key":"2025081809000536000_2025.08.13.25333123v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(19)30320-5"},{"key":"2025081809000536000_2025.08.13.25333123v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(08)70117-0"},{"key":"2025081809000536000_2025.08.13.25333123v1.4","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a009407"},{"key":"2025081809000536000_2025.08.13.25333123v1.5","doi-asserted-by":"crossref","first-page":"548","DOI":"10.3390\/jcm4040548","article-title":"Using 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