PUBLICATION

CHCHD10^P80L knock-in zebrafish display a mild ALS-like phenotype

Authors

Légaré, V.P., Harji, Z.A., Rampal, C.J., Antonicka, H., Gurberg, T.J.N., Persia, O., Rodríguez, E.C., Shoubridge, E.A., Armstrong, G.A.B.

ID

ZDB-PUB-240912-7

Date

2024

Source

Experimental neurology 382: 114945 (Journal)

Registered Authors

Armstrong, Gary A.B.

Keywords

Als, CHCHD10, Knock-in mutation, Mitochondria, Motor neuron, Neurodegeneration, Zebrafish

MeSH Terms

Amyotrophic Lateral Sclerosis*/genetics
Amyotrophic Lateral Sclerosis*/pathology
Mitochondrial Proteins*/genetics
Zebrafish Proteins/genetics
Disease Models, Animal
Phenotype*
Animals
Animals, Genetically Modified
Gene Knock-In Techniques
Zebrafish*
Neuromuscular Junction/genetics
Neuromuscular Junction/metabolism
Neuromuscular Junction/pathology
Motor Neurons/metabolism
Motor Neurons/pathology

PubMed

39260590 Full text @ Exp. Neurol.

Abstract

Mutations in the nuclear-encoded mitochondrial gene CHCHD10 have been observed in patients with a spectrum of diseases that include amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). To investigate the pathogenic nature of disease-associated variants of CHCHD10 we generated a zebrafish knock-in (KI) model expressing the orthologous ALS-associated CHCHD10^P80L variant (zebrafish: Chchd10^P83L). Larval chchd10^P83L/P83L fish displayed reduced Chchd10 protein expression levels, motor impairment, reduced survival and abnormal neuromuscular junctions (NMJ). These deficits were not accompanied by changes in transcripts involved in the integrated stress response (ISR), phenocopying previous findings in our knockout (chchd10^-/-). Adult, 11-month old chchd10^P83L/P83L zebrafish, displayed smaller slow- and fast-twitch muscle cell cross-sectional areas compared to wild type zebrafish muscle cells. Motoneurons in the spinal cord of chchd10^P83L/P83L zebrafish displayed similar cross-sectional areas to that of wild type motor neurons and significantly fewer motor neurons were observed when compared to chchd2^-/- adult spinal cords. Bulk RNA sequencing using whole spinal cords of 7-month old fish revealed transcriptional changes associated with neuroinflammation, apoptosis, amino acid metabolism and mt-DNA inflammatory response in our chchd10^P83L/P83L model. The findings presented here, suggest that the CHCHD10^P80L variant confers an ALS-like phenotype when expressed in zebrafish.

Genes / Markers

Figures