TY  - JOUR
AU  - de Calbiac, Hortense
AU  - Renault, Solène
AU  - Haouy, Grégoire
AU  - Jung, Vincent
AU  - Roger, Kevin
AU  - Zhou, Qihui
AU  - Campanari, Maria-Letizia
AU  - Chentout, Loïc
AU  - Demy, Doris Lou
AU  - Marian, Anca
AU  - Goudin, Nicolas
AU  - Edbauer, Dieter
AU  - Guerrera, Chiara
AU  - Ciura, Sorana
AU  - Kabashi, Edor
TI  - Poly-GP accumulation due to C9orf72 loss of function induces motor neuron apoptosis through autophagy and mitophagy defects.
JO  - Autophagy
VL  - 20
IS  - 10
SN  - 1554-8627
CY  - Abingdon, Oxon
PB  - Taylor & Francis
M1  - DZNE-2024-01165
SP  - 2164 - 2185
PY  - 2024
AB  - 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.
KW  - Motor Neurons: metabolism
KW  - Motor Neurons: pathology
KW  - Animals
KW  - C9orf72 Protein: genetics
KW  - C9orf72 Protein: metabolism
KW  - Zebrafish
KW  - Mitophagy: genetics
KW  - Apoptosis: genetics
KW  - Humans
KW  - Autophagy: genetics
KW  - Autophagy: physiology
KW  - Amyotrophic Lateral Sclerosis: metabolism
KW  - Amyotrophic Lateral Sclerosis: pathology
KW  - Amyotrophic Lateral Sclerosis: genetics
KW  - Dipeptides: pharmacology
KW  - Dipeptides: metabolism
KW  - Loss of Function Mutation: genetics
KW  - Mitochondria: metabolism
KW  - Disease Models, Animal
KW  - Amyotrophic lateral sclerosis (Other)
KW  - apoptosis (Other)
KW  - mitochondria (Other)
KW  - motor neuron (Other)
KW  - neurodegeneration (Other)
KW  - poly-GP (Other)
KW  - C9orf72 Protein (NLM Chemicals)
KW  - Dipeptides (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC11423671
C6  - pmid:39316747
DO  - DOI:10.1080/15548627.2024.2358736
UR  - https://pub.dzne.de/record/272348
ER  -