{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T17:07:54Z","timestamp":1790874474460,"version":"4.1.0"},"posted":{"date-parts":[[2024,3,5]]},"group-title":"Genomics","reference-count":93,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,3,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Whether neurodegenerative diseases linked to misfolding of the same protein share genetic risk drivers or whether different protein-aggregation pathologies in neurodegeneration are mechanistically related remains uncertain. Conventional genetic analyses are underpowered to address these questions. Through careful selection of patients based on protein aggregation phenotype (rather than clinical diagnosis) we can increase statistical power to detect associated variants in a targeted set of genes that modify proteotoxicities. Genetic modifiers of alpha-synuclein (\u0251S) and beta-amyloid (A\u03b2) cytotoxicity in yeast are enriched in risk factors for Parkinson\u2019s disease (PD) and Alzheimer\u2019s disease (AD), respectively. Here, along with known AD\/PD risk genes, we deeply sequenced exomes of 430 \u0251S\/A\u03b2 modifier genes in patients across alpha-synucleinopathies (PD, Lewy body dementia and multiple system atrophy). Beyond known PD genes\n                  <jats:italic>GBA1<\/jats:italic>\n                  and\n                  <jats:italic>LRRK2<\/jats:italic>\n                  , rare variants AD genes (\n                  <jats:italic>CD33<\/jats:italic>\n                  ,\n                  <jats:italic>CR1<\/jats:italic>\n                  and\n                  <jats:italic>PSEN2<\/jats:italic>\n                  ) and A\u03b2 toxicity modifiers involved in RhoA\/actin cytoskeleton regulation (\n                  <jats:italic>ARGHEF1, ARHGEF28, MICAL3, PASK, PKN2, PSEN2<\/jats:italic>\n                  ) were shared risk factors across synucleinopathies. Actin pathology occurred in iPSC synucleinopathy models and RhoA downregulation exacerbated \u0251S pathology. Even in sporadic PD, the expression of these genes was altered across CNS cell types. Genome-wide CRISPR screens revealed the essentiality of\n                  <jats:italic>PSEN2<\/jats:italic>\n                  in both human cortical and dopaminergic neurons, and\n                  <jats:italic>PSEN2<\/jats:italic>\n                  mutation carriers exhibited diffuse brainstem and cortical synucleinopathy independent of AD pathology.\n                  <jats:italic>PSEN2<\/jats:italic>\n                  contributes to a common-risk signal in PD GWAS and regulates \u0251S expression in neurons. Our results identify convergent mechanisms across synucleinopathies, some shared with AD.\n                <\/jats:p>","DOI":"10.1101\/2024.03.03.583145","type":"posted-content","created":{"date-parts":[[2024,3,5]],"date-time":"2024-03-05T14:50:16Z","timestamp":1709650216000},"source":"Crossref","is-referenced-by-count":4,"title":["Deep sequencing of proteotoxicity modifier genes uncovers a Presenilin-2\/beta-amyloid-actin genetic risk module shared among alpha-synucleinopathies"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6313-6357","authenticated-orcid":false,"given":"Sumaiya","family":"Nazeen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3107-8359","authenticated-orcid":false,"given":"Xinyuan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dina","family":"Zielinski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6247-8080","authenticated-orcid":false,"given":"Isabel","family":"Lam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erinc","family":"Hallacli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Ethier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronya","family":"Strom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camila 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