{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T16:07:42Z","timestamp":1777478862176,"version":"3.51.4"},"posted":{"date-parts":[[2024,9,1]]},"group-title":"Cell Biology","reference-count":105,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,9,1]],"date-time":"2024-09-01T00:00:00Z","timestamp":1725148800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,9,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Alpha-synuclein (\u03b1Syn) is an intrinsically disordered protein that accumulates in the brains of patients with Parkinson\u2019s disease and forms intraneuronal inclusions called Lewy Bodies. While the mechanism underlying the dysregulation of \u03b1Syn in Parkinson\u2019s disease is unclear, it is thought that prionoid cell-to-cell propagation of \u03b1Syn has an important role. Through a high throughput screen, we recently identified 38 genes whose knock down modulates \u03b1Syn propagation. Follow up experiments were undertaken for two of those genes,\n                  <jats:italic>TAX1BP1<\/jats:italic>\n                  and\n                  <jats:italic>ADAMTS19<\/jats:italic>\n                  , to study the mechanism with which they regulate \u03b1Syn homeostasis. We used a recently developed M17D neuroblastoma cell line expressing triple mutant (E35K+E46K+E61K) \u201c3K\u201d \u03b1Syn under doxycycline induction. 3K \u03b1Syn spontaneously forms inclusions that show ultrastructural similarities to Lewy Bodies. Experiments using that cell line showed that\n                  <jats:italic>TAX1BP1<\/jats:italic>\n                  and\n                  <jats:italic>ADAMTS19<\/jats:italic>\n                  regulate how \u03b1Syn interacts with lipids and phase separates into inclusions, respectively, adding to the growing body of evidence implicating those processes in Parkinson\u2019s disease. Through RNA sequencing, we identified several genes that are differentially expressed after knock-down of\n                  <jats:italic>TAX1BP1<\/jats:italic>\n                  or\n                  <jats:italic>ADAMTS19<\/jats:italic>\n                  . Burden analysis revealed that those differentially expressed genes (DEGs) carry an increased frequency of rare risk variants in Parkinson\u2019s disease patients versus healthy controls, an effect that was independently replicated across two separate cohorts (GP2 and AMP-PD). Weighted gene co-expression network analysis (WGCNA) showed that the DEGs cluster within modules in regions of the brain that develop high degrees of \u03b1Syn pathology (basal ganglia, cortex). We propose a novel model for the genetic architecture of sporadic Parkinson\u2019s disease: increased burden of risk variants across genetic networks dysregulates pathways underlying \u03b1Syn homeostasis, thereby leading to pathology and neurodegeneration.\n                <\/jats:p>","DOI":"10.1101\/2024.08.30.610195","type":"posted-content","created":{"date-parts":[[2024,9,1]],"date-time":"2024-09-01T12:25:11Z","timestamp":1725193511000},"source":"Crossref","is-referenced-by-count":1,"title":["Increased burden of rare risk variants across gene expression networks predisposes to sporadic Parkinson\u2019s disease"],"prefix":"10.64898","author":[{"given":"Elena","family":"Eubanks","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katelyn","family":"VanderSleen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiya","family":"Mody","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neha","family":"Patel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin","family":"Sacks","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mahsa Darestani","family":"Farahani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinying","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jordan","family":"Elliott","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nora","family":"Jaber","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fulya","family":"Ak\u00e7imen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Bandres-Ciga","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fadel","family":"Helweh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanjana","family":"Archakam","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Kimelman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bineet","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philip","family":"Socha","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ananya","family":"Guntur","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tim","family":"Bartels","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulf","family":"Dettmer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. 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