PUBLICATION
HNRNPK alleviates RNA toxicity by counteracting DNA damage in C9orf72 ALS
- Authors
- Braems, E., Bercier, V., Van Schoor, E., Heeren, K., Beckers, J., Fumagalli, L., Dedeene, L., Moisse, M., Geudens, I., Hersmus, N., Mehta, A.R., Selvaraj, B.T., Chandran, S., Ho, R., Thal, D.R., Van Damme, P., Swinnen, B., Van Den Bosch, L.
- ID
- ZDB-PUB-220728-34
- Date
- 2022
- Source
- Acta Neuropathologica 144(3): 465-488 (Journal)
- Registered Authors
- Bercier, Valérie
- Keywords
- ALS, C9orf72, DNA damage, HNRNPK, RNA toxicity, RRM2
- MeSH Terms
-
- Amyotrophic Lateral Sclerosis*/pathology
- Animals
- C9orf72 Protein/genetics
- C9orf72 Protein/metabolism
- DNA Damage
- DNA Repeat Expansion/genetics
- Frontotemporal Dementia*/pathology
- Heterogeneous-Nuclear Ribonucleoprotein K/genetics
- Heterogeneous-Nuclear Ribonucleoprotein K/metabolism
- Pick Disease of the Brain*/genetics
- RNA/metabolism
- RNA, Antisense
- Zebrafish/genetics
- Zebrafish/metabolism
- PubMed
- 35895140 Full text @ Acta Neuropathol.
Citation
Braems, E., Bercier, V., Van Schoor, E., Heeren, K., Beckers, J., Fumagalli, L., Dedeene, L., Moisse, M., Geudens, I., Hersmus, N., Mehta, A.R., Selvaraj, B.T., Chandran, S., Ho, R., Thal, D.R., Van Damme, P., Swinnen, B., Van Den Bosch, L. (2022) HNRNPK alleviates RNA toxicity by counteracting DNA damage in C9orf72 ALS. Acta Neuropathologica. 144(3):465-488.
Abstract
A 'GGGGCC' repeat expansion in the first intron of the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The exact mechanism resulting in these neurodegenerative diseases remains elusive, but C9 repeat RNA toxicity has been implicated as a gain-of-function mechanism. Our aim was to use a zebrafish model for C9orf72 RNA toxicity to identify modifiers of the ALS-linked phenotype. We discovered that the RNA-binding protein heterogeneous nuclear ribonucleoprotein K (HNRNPK) reverses the toxicity of both sense and antisense repeat RNA, which is dependent on its subcellular localization and RNA recognition, and not on C9orf72 repeat RNA binding. We observed HNRNPK cytoplasmic mislocalization in C9orf72 ALS patient fibroblasts, induced pluripotent stem cell (iPSC)-derived motor neurons and post-mortem motor cortex and spinal cord, in line with a disrupted HNRNPK function in C9orf72 ALS. In C9orf72 ALS/FTD patient tissue, we discovered an increased nuclear translocation, but reduced expression of ribonucleotide reductase regulatory subunit M2 (RRM2), a downstream target of HNRNPK involved in the DNA damage response. Last but not least, we showed that increasing the expression of HNRNPK or RRM2 was sufficient to mitigate DNA damage in our C9orf72 RNA toxicity zebrafish model. Overall, our study strengthens the relevance of RNA toxicity as a pathogenic mechanism in C9orf72 ALS and demonstrates its link with an aberrant DNA damage response, opening novel therapeutic avenues for C9orf72 ALS/FTD.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping