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CRISPR/Cas9 screen in human iPSC‐derived cortical neurons identifies NEK6 as a novel disease modifier of C9orf72 poly(PR) toxicity
Author(s) -
Guo Wenting,
Wang Haibo,
Kumar Tharkeshwar Arun,
Couthouis Julien,
Braems Elke,
Masrori Pegah,
Van Schoor Evelien,
Fan Yannan,
Ahuja Karan,
Moisse Matthieu,
Jacquemyn Maarten,
Furtado Madeiro da Costa Rodrigo,
Gajjar Madhavsai,
Balusu Sriram,
Tricot Tine,
Fumagalli Laura,
Hersmus Nicole,
Janky Rekin's,
Impens Francis,
Vanden Berghe Pieter,
Ho Ritchie,
Thal Dietmar Rudolf,
Vandenberghe Rik,
Hegde Muralidhar L.,
Chandran Siddharthan,
De Strooper Bart,
Daelemans Dirk,
Van Damme Philip,
Van Den Bosch Ludo,
Verfaillie Catherine
Publication year - 2023
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.12760
Subject(s) - c9orf72 , induced pluripotent stem cell , neurodegeneration , biology , microbiology and biotechnology , trinucleotide repeat expansion , chemistry , genetics , gene , medicine , embryonic stem cell , allele , disease , pathology
The most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are hexanucleotide repeats in chromosome 9 open reading frame 72 ( C9orf72) . These repeats produce dipeptide repeat proteins with poly(PR) being the most toxic one. Methods We performed a kinome‐wide CRISPR/Cas9 knock‐out screen in human induced pluripotent stem cell (iPSC) ‐derived cortical neurons to identify modifiers of poly(PR) toxicity, and validated the role of candidate modifiers using in vitro, in vivo, and ex‐vivo studies. Results Knock‐down of NIMA‐related kinase 6 (NEK6) prevented neuronal toxicity caused by poly(PR). Knock‐down of nek6 also ameliorated the poly(PR)‐induced axonopathy in zebrafish and NEK6 was aberrantly expressed in C9orf72 patients. Suppression of NEK6 expression and NEK6 activity inhibition rescued axonal transport defects in cortical neurons from C9orf72 patient iPSCs, at least partially by reversing p53‐related DNA damage. Discussion We identified NEK6, which regulates poly(PR)‐mediated p53‐related DNA damage, as a novel therapeutic target for C9orf72 FTD/ALS.