Advanced search
1 file | 2.73 MB Add to list

CRISPR/Cas9 screen in human iPSC-derived cortical neurons identifies NEK6 as a novel disease modifier of C9orf72 poly(PR) toxicity

(2023) ALZHEIMERS & DEMENTIA. 19(4). p.1245-1259
Author
Organization
Abstract
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.
Keywords
amyotrophic lateral sclerosis, C9orf72, CRISPR, Cas9 screen, DNA damage, frontotemporal dementia, human pluripotent stem cells, NEK6, neurodegeneration, p53, PR toxicity, P53 TRANSACTIVATION DOMAIN, NEURODEGENERATION, REGULATOR, BINDING, KINASES, CELLS

Downloads

  • Alzheimer s Dementia - 2022 - Guo - CRISPR Cas9 screen in human iPSC‐derived cortical neurons identifies NEK6 as a novel.pdf
    • full text (Published version)
    • |
    • open access
    • |
    • PDF
    • |
    • 2.73 MB

Citation

Please use this url to cite or link to this publication:

MLA
Guo, W., et al. “CRISPR/Cas9 Screen in Human IPSC-Derived Cortical Neurons Identifies NEK6 as a Novel Disease Modifier of C9orf72 Poly(PR) Toxicity.” ALZHEIMERS & DEMENTIA, vol. 19, no. 4, 2023, pp. 1245–59, doi:10.1002/alz.12760.
APA
Guo, W., Wang, H., Kumar Tharkeshwar, A., Couthouis, J., Braems, E., Masrori, P., … Verfaillie, C. (2023). CRISPR/Cas9 screen in human iPSC-derived cortical neurons identifies NEK6 as a novel disease modifier of C9orf72 poly(PR) toxicity. ALZHEIMERS & DEMENTIA, 19(4), 1245–1259. https://doi.org/10.1002/alz.12760
Chicago author-date
Guo, W, H Wang, A Kumar Tharkeshwar, J Couthouis, E Braems, P Masrori, E Van Schoor, et al. 2023. “CRISPR/Cas9 Screen in Human IPSC-Derived Cortical Neurons Identifies NEK6 as a Novel Disease Modifier of C9orf72 Poly(PR) Toxicity.” ALZHEIMERS & DEMENTIA 19 (4): 1245–59. https://doi.org/10.1002/alz.12760.
Chicago author-date (all authors)
Guo, W, H Wang, A Kumar Tharkeshwar, J Couthouis, E Braems, P Masrori, E Van Schoor, Y Fan, K Ahuja, M Moisse, M Jacquemyn, R Furtado Madeiro da Costa, M Gajjar, S Balusu, T Tricot, L Fumagalli, N Hersmus, R Janky, Francis Impens, P Vanden Berghe, R Ho, DR Thal, R Vandenberghe, ML Hegde, S Chandran, B De Strooper, D Daelemans, P Van Damme, L Van Den Bosch, and C Verfaillie. 2023. “CRISPR/Cas9 Screen in Human IPSC-Derived Cortical Neurons Identifies NEK6 as a Novel Disease Modifier of C9orf72 Poly(PR) Toxicity.” ALZHEIMERS & DEMENTIA 19 (4): 1245–1259. doi:10.1002/alz.12760.
Vancouver
1.
Guo W, Wang H, Kumar Tharkeshwar A, Couthouis J, Braems E, Masrori P, et al. CRISPR/Cas9 screen in human iPSC-derived cortical neurons identifies NEK6 as a novel disease modifier of C9orf72 poly(PR) toxicity. ALZHEIMERS & DEMENTIA. 2023;19(4):1245–59.
IEEE
[1]
W. Guo et al., “CRISPR/Cas9 screen in human iPSC-derived cortical neurons identifies NEK6 as a novel disease modifier of C9orf72 poly(PR) toxicity,” ALZHEIMERS & DEMENTIA, vol. 19, no. 4, pp. 1245–1259, 2023.
@article{8764285,
  abstract     = {{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.}},
  author       = {{Guo, W and Wang, H and Kumar Tharkeshwar, A and Couthouis, J and Braems, E and Masrori, P and Van Schoor, E and Fan, Y and Ahuja, K and Moisse, M and Jacquemyn, M and Furtado Madeiro da Costa, R and Gajjar, M and Balusu, S and Tricot, T and Fumagalli, L and Hersmus, N and Janky, R and Impens, Francis and Vanden Berghe, P and Ho, R and Thal, DR and Vandenberghe, R and Hegde, ML and Chandran, S and De Strooper, B and Daelemans, D and Van Damme, P and Van Den Bosch, L and Verfaillie, C}},
  issn         = {{1552-5260}},
  journal      = {{ALZHEIMERS & DEMENTIA}},
  keywords     = {{amyotrophic lateral sclerosis,C9orf72,CRISPR,Cas9 screen,DNA damage,frontotemporal dementia,human pluripotent stem cells,NEK6,neurodegeneration,p53,PR toxicity,P53 TRANSACTIVATION DOMAIN,NEURODEGENERATION,REGULATOR,BINDING,KINASES,CELLS}},
  language     = {{eng}},
  number       = {{4}},
  pages        = {{1245--1259}},
  title        = {{CRISPR/Cas9 screen in human iPSC-derived cortical neurons identifies NEK6 as a novel disease modifier of C9orf72 poly(PR) toxicity}},
  url          = {{http://doi.org/10.1002/alz.12760}},
  volume       = {{19}},
  year         = {{2023}},
}

Altmetric
View in Altmetric
Web of Science
Times cited: