PUBLICATION
Poly-GP accumulation due to C9orf72 loss of function induces motor neuron apoptosis through autophagy and mitophagy defects
- Authors
- de Calbiac, H., Renault, S., Haouy, G., Jung, V., Roger, K., Zhou, Q., Campanari, M.L., Chentout, L., Demy, D.L., Marian, A., Goudin, N., Edbauer, D., Guerrera, C., Ciura, S., Kabashi, E.
- ID
- ZDB-PUB-240925-5
- Date
- 2024
- Source
- Autophagy 20: 216421852164-2185 (Journal)
- Registered Authors
- Demy, Doris-Lou
- Keywords
- Amyotrophic lateral sclerosis, apoptosis, mitochondria, motor neuron, neurodegeneration, poly-GP
- MeSH Terms
-
- Disease Models, Animal
- Mitochondria/metabolism
- Motor Neurons*/metabolism
- Motor Neurons*/pathology
- Humans
- Animals
- Autophagy*/genetics
- Autophagy*/physiology
- Dipeptides*/metabolism
- Dipeptides*/pharmacology
- Mitophagy*/genetics
- Apoptosis*/genetics
- Amyotrophic Lateral Sclerosis*/genetics
- Amyotrophic Lateral Sclerosis*/metabolism
- Amyotrophic Lateral Sclerosis*/pathology
- C9orf72 Protein*/genetics
- C9orf72 Protein*/metabolism
- Zebrafish*
- Loss of Function Mutation/genetics
- PubMed
- 39316747 Full text @ Autophagy
Citation
de Calbiac, H., Renault, S., Haouy, G., Jung, V., Roger, K., Zhou, Q., Campanari, M.L., Chentout, L., Demy, D.L., Marian, A., Goudin, N., Edbauer, D., Guerrera, C., Ciura, S., Kabashi, E. (2024) Poly-GP accumulation due to C9orf72 loss of function induces motor neuron apoptosis through autophagy and mitophagy defects. Autophagy. 20:216421852164-2185.
Abstract
The GGGGCC hexanucleotide repeat expansion (HRE) of the C9orf72 gene is the most frequent cause of amyotrophic lateral sclerosis (ALS), a devastative neurodegenerative disease characterized by motor neuron degeneration. C9orf72 HRE is associated with lowered levels of C9orf72 expression and its translation results in the production of dipeptide-repeats (DPRs). To recapitulate C9orf72-related ALS disease in vivo, we developed a zebrafish model where we expressed glycine-proline (GP) DPR in a c9orf72 knockdown context. We report that C9orf72 gain- and loss-of-function properties act synergistically to induce motor neuron degeneration and paralysis with poly(GP) accumulating preferentially within motor neurons along with Sqstm1/p62 aggregation indicating macroautophagy/autophagy deficits. Poly(GP) levels were shown to accumulate upon c9orf72 downregulation and were comparable to levels assessed in autopsy samples of patients carrying C9orf72 HRE. Chemical boosting of autophagy using rapamycin or apilimod, is able to rescue motor deficits. Proteomics analysis of zebrafish-purified motor neurons unravels mitochondria dysfunction confirmed through a comparative analysis of previously published C9orf72 iPSC-derived motor neurons. Consistently, 3D-reconstructions of motor neuron demonstrate that poly(GP) aggregates colocalize to mitochondria, thus inducing their elongation and swelling and the failure of their processing by mitophagy, with mitophagy activation through urolithin A preventing locomotor deficits. Finally, we report apoptotic-related increased amounts of cleaved Casp3 (caspase 3, apoptosis-related cysteine peptidase) and rescue of motor neuron degeneration by constitutive inhibition of Casp9 or treatment with decylubiquinone. Here we provide evidence of key pathogenic steps in C9ALS-FTD that can be targeted through pharmacological avenues, thus raising new therapeutic perspectives for ALS patients.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping