CRISPR/Cas9 screen in human iPSC‐derived cortical neurons identifies NEK6 as a novel disease modifier of C9orf72 poly(PR) toxicity
W Guo, H Wang, A Kumar Tharkeshwar… - Alzheimer's & …, 2023 - Wiley Online Library
Alzheimer's & Dementia, 2023•Wiley Online Library
Introduction 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 …
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 …
Introduction
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.
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