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Deep sequencing of proteotoxicity modifier genes uncovers a Presenilin-2/beta-amyloid-actin genetic risk module shared among alpha-synucleinopathies.
Nazeen, Sumaiya; Wang, Xinyuan; Zielinski, Dina; Lam, Isabel; Hallacli, Erinc; Xu, Ping; Ethier, Elizabeth; Strom, Ronya; Zanella, Camila A; Nithianandam, Vanitha; Ritter, Dylan; Henderson, Alexander; Saurat, Nathalie; Afroz, Jalwa; Nutter-Upham, Andrew; Benyamini, Hadar; Copty, Joseph; Ravishankar, Shyamsundar; Morrow, Autumn; Mitchel, Jonathan; Neavin, Drew; Gupta, Renuka; Farbehi, Nona; Grundman, Jennifer; Myers, Richard H; Scherzer, Clemens R; Trojanowski, John Q; Van Deerlin, Vivianna M; Cooper, Antony A; Lee, Edward B; Erlich, Yaniv; Lindquist, Susan; Peng, Jian; Geschwind, Daniel H; Powell, Joseph; Studer, Lorenz; Feany, Mel B; Sunyaev, Shamil R; Khurana, Vikram.
Afiliação
  • Nazeen S; Division of Movement Disorders, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Wang X; Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Zielinski D; Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
  • Lam I; Division of Movement Disorders, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Hallacli E; Division of Movement Disorders, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Xu P; Whitehead Institute of Biomedical Research, Cambridge, MA, USA.
  • Ethier E; Division of Movement Disorders, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Strom R; Division of Movement Disorders, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Zanella CA; Division of Movement Disorders, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Nithianandam V; Division of Movement Disorders, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Ritter D; Division of Movement Disorders, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Henderson A; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Saurat N; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Afroz J; The Center for Stem Cell Biology, Sloan-Kettering Institute for Cancer Research, New York, NY, USA.
  • Nutter-Upham A; The Center for Stem Cell Biology, Sloan-Kettering Institute for Cancer Research, New York, NY, USA.
  • Benyamini H; The Center for Stem Cell Biology, Sloan-Kettering Institute for Cancer Research, New York, NY, USA.
  • Copty J; The Center for Stem Cell Biology, Sloan-Kettering Institute for Cancer Research, New York, NY, USA.
  • Ravishankar S; Whitehead Institute of Biomedical Research, Cambridge, MA, USA.
  • Morrow A; Whitehead Institute of Biomedical Research, Cambridge, MA, USA.
  • Mitchel J; Garvan Institute of Medical Research, Sydney, NSW, Australia.
  • Neavin D; Garvan Institute of Medical Research, Sydney, NSW, Australia.
  • Gupta R; Division of Movement Disorders, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Farbehi N; Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
  • Grundman J; Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
  • Myers RH; Program in Health Sciences & Technology, Harvard Medical School & Massachusetts Institute of Technology, Boston, MA.
  • Scherzer CR; Garvan Institute of Medical Research, Sydney, NSW, Australia.
  • Trojanowski JQ; Garvan Institute of Medical Research, Sydney, NSW, Australia.
  • Van Deerlin VM; Garvan Institute of Medical Research, Sydney, NSW, Australia.
  • Cooper AA; Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
  • Lee EB; Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
  • Erlich Y; Division of Movement Disorders, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Lindquist S; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
  • Peng J; Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, PA, USA.
  • Geschwind DH; Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, PA, USA.
  • Powell J; Garvan Institute of Medical Research, Sydney, NSW, Australia.
  • Studer L; Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, PA, USA.
  • Feany MB; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Sunyaev SR; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Khurana V; Department of Computer Science, University of Illinois Urbana-Champaign, Champaign, IL, USA.
bioRxiv ; 2024 Mar 07.
Article em En | MEDLINE | ID: mdl-38496508
ABSTRACT
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 (ɑS) and beta-amyloid (Aß) cytotoxicity in yeast are enriched in risk factors for Parkinson's disease (PD) and Alzheimer's disease (AD), respectively. Here, along with known AD/PD risk genes, we deeply sequenced exomes of 430 ɑS/Aß modifier genes in patients across alpha-synucleinopathies (PD, Lewy body dementia and multiple system atrophy). Beyond known PD genes GBA1 and LRRK2, rare variants AD genes (CD33, CR1 and PSEN2) and Aß toxicity modifiers involved in RhoA/actin cytoskeleton regulation (ARGHEF1, ARHGEF28, MICAL3, PASK, PKN2, PSEN2) were shared risk factors across synucleinopathies. Actin pathology occurred in iPSC synucleinopathy models and RhoA downregulation exacerbated ɑS pathology. Even in sporadic PD, the expression of these genes was altered across CNS cell types. Genome-wide CRISPR screens revealed the essentiality of PSEN2 in both human cortical and dopaminergic neurons, and PSEN2 mutation carriers exhibited diffuse brainstem and cortical synucleinopathy independent of AD pathology. PSEN2 contributes to a common-risk signal in PD GWAS and regulates ɑS expression in neurons. Our results identify convergent mechanisms across synucleinopathies, some shared with AD.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Ano de publicação: 2024 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Ano de publicação: 2024 Tipo de documento: Article