Home > Publications Database > Poly-GP accumulation due to C9orf72 loss of function induces motor neuron apoptosis through autophagy and mitophagy defects. > print

001     272348
005     20250127091519.0
024 7 _ |a pmc:PMC11423671
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024 7 _ |a 10.1080/15548627.2024.2358736
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024 7 _ |a pmid:39316747
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024 7 _ |a 1554-8627
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024 7 _ |a 1538-4101
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037 _ _ |a DZNE-2024-01165
041 _ _ |a English
082 _ _ |a 570
100 1 _ |a de Calbiac, Hortense
|0 0000-0002-6246-0833
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245 _ _ |a Poly-GP accumulation due to C9orf72 loss of function induces motor neuron apoptosis through autophagy and mitophagy defects.
260 _ _ |a Abingdon, Oxon
|c 2024
|b Taylor & Francis
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520 _ _ |a 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.
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650 _ 7 |a Amyotrophic lateral sclerosis
|2 Other
650 _ 7 |a apoptosis
|2 Other
650 _ 7 |a mitochondria
|2 Other
650 _ 7 |a motor neuron
|2 Other
650 _ 7 |a neurodegeneration
|2 Other
650 _ 7 |a poly-GP
|2 Other
650 _ 7 |a C9orf72 Protein
|2 NLM Chemicals
650 _ 7 |a Dipeptides
|2 NLM Chemicals
650 _ 2 |a Motor Neurons: metabolism
|2 MeSH
650 _ 2 |a Motor Neurons: pathology
|2 MeSH
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a C9orf72 Protein: genetics
|2 MeSH
650 _ 2 |a C9orf72 Protein: metabolism
|2 MeSH
650 _ 2 |a Zebrafish
|2 MeSH
650 _ 2 |a Mitophagy: genetics
|2 MeSH
650 _ 2 |a Apoptosis: genetics
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Autophagy: genetics
|2 MeSH
650 _ 2 |a Autophagy: physiology
|2 MeSH
650 _ 2 |a Amyotrophic Lateral Sclerosis: metabolism
|2 MeSH
650 _ 2 |a Amyotrophic Lateral Sclerosis: pathology
|2 MeSH
650 _ 2 |a Amyotrophic Lateral Sclerosis: genetics
|2 MeSH
650 _ 2 |a Dipeptides: pharmacology
|2 MeSH
650 _ 2 |a Dipeptides: metabolism
|2 MeSH
650 _ 2 |a Loss of Function Mutation: genetics
|2 MeSH
650 _ 2 |a Mitochondria: metabolism
|2 MeSH
650 _ 2 |a Disease Models, Animal
|2 MeSH
700 1 _ |a Renault, Solène
|b 1
700 1 _ |a Haouy, Grégoire
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700 1 _ |a Jung, Vincent
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700 1 _ |a Roger, Kevin
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700 1 _ |a Zhou, Qihui
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700 1 _ |a Campanari, Maria-Letizia
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700 1 _ |a Chentout, Loïc
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700 1 _ |a Demy, Doris Lou
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700 1 _ |a Marian, Anca
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700 1 _ |a Goudin, Nicolas
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700 1 _ |a Edbauer, Dieter
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700 1 _ |a Guerrera, Chiara
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700 1 _ |a Ciura, Sorana
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700 1 _ |a Kabashi, Edor
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773 _ _ |a 10.1080/15548627.2024.2358736
|g Vol. 20, no. 10, p. 2164 - 2185
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|t Autophagy
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|x 1554-8627
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910 1 _ |a Deutsches Zentrum für Neurodegenerative Erkrankungen
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