Related Experiment Video
Updated: Aug 31, 2025
CRISPR/Cas9 Editing of the C. elegans rbm-3.2 Gene using the dpy-10 Co-CRISPR Screening Marker and Assembled Ribonucleoprotein Complexes.
Published on: December 11, 2020
CRISPR/Cas9 screen in human iPSC-derived cortical neurons identifies NEK6 as a novel disease modifier of C9orf72
Wenting Guo1,2,3, Haibo Wang4,5, Arun Kumar Tharkeshwar2,3
1Stem Cell Institute, Department of Devolpment and Regeneration, KU Leuven, Leuven, Belgium.
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.
More Related Videos
13:47Lentiviral Vector Platform for the Efficient Delivery of Epigenome-editing Tools into Human Induced Pluripotent Stem Cell-derived Disease Models
Published on: March 29, 2019
11:49Author Spotlight: Establishing CENP-E Knockout HeLa Cells – A Novel Approach to Study Kinesin-7 CENP-E Biology and its Inhibitors
Published on: June 23, 2023
Related Concept Videos
01:59CRISPR
01:28CRISPR/Cas9 Genome Editing