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000272348 1001_ $$00000-0002-6246-0833$$ade Calbiac, Hortense$$b0
000272348 245__ $$aPoly-GP accumulation due to C9orf72 loss of function induces motor neuron apoptosis through autophagy and mitophagy defects.
000272348 260__ $$aAbingdon, Oxon$$bTaylor & Francis$$c2024
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000272348 520__ $$aThe 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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000272348 650_7 $$2Other$$aAmyotrophic lateral sclerosis
000272348 650_7 $$2Other$$aapoptosis
000272348 650_7 $$2Other$$amitochondria
000272348 650_7 $$2Other$$amotor neuron
000272348 650_7 $$2Other$$aneurodegeneration
000272348 650_7 $$2Other$$apoly-GP
000272348 650_7 $$2NLM Chemicals$$aC9orf72 Protein
000272348 650_7 $$2NLM Chemicals$$aDipeptides
000272348 650_2 $$2MeSH$$aMotor Neurons: metabolism
000272348 650_2 $$2MeSH$$aMotor Neurons: pathology
000272348 650_2 $$2MeSH$$aAnimals
000272348 650_2 $$2MeSH$$aC9orf72 Protein: genetics
000272348 650_2 $$2MeSH$$aC9orf72 Protein: metabolism
000272348 650_2 $$2MeSH$$aZebrafish
000272348 650_2 $$2MeSH$$aMitophagy: genetics
000272348 650_2 $$2MeSH$$aApoptosis: genetics
000272348 650_2 $$2MeSH$$aHumans
000272348 650_2 $$2MeSH$$aAutophagy: genetics
000272348 650_2 $$2MeSH$$aAutophagy: physiology
000272348 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: metabolism
000272348 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: pathology
000272348 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: genetics
000272348 650_2 $$2MeSH$$aDipeptides: pharmacology
000272348 650_2 $$2MeSH$$aDipeptides: metabolism
000272348 650_2 $$2MeSH$$aLoss of Function Mutation: genetics
000272348 650_2 $$2MeSH$$aMitochondria: metabolism
000272348 650_2 $$2MeSH$$aDisease Models, Animal
000272348 7001_ $$aRenault, Solène$$b1
000272348 7001_ $$aHaouy, Grégoire$$b2
000272348 7001_ $$aJung, Vincent$$b3
000272348 7001_ $$aRoger, Kevin$$b4
000272348 7001_ $$0P:(DE-2719)2811347$$aZhou, Qihui$$b5$$udzne
000272348 7001_ $$aCampanari, Maria-Letizia$$b6
000272348 7001_ $$aChentout, Loïc$$b7
000272348 7001_ $$aDemy, Doris Lou$$b8
000272348 7001_ $$aMarian, Anca$$b9
000272348 7001_ $$aGoudin, Nicolas$$b10
000272348 7001_ $$0P:(DE-2719)2231621$$aEdbauer, Dieter$$b11$$udzne
000272348 7001_ $$aGuerrera, Chiara$$b12
000272348 7001_ $$aCiura, Sorana$$b13
000272348 7001_ $$aKabashi, Edor$$b14
000272348 773__ $$0PERI:(DE-600)2262043-6$$a10.1080/15548627.2024.2358736$$gVol. 20, no. 10, p. 2164 - 2185$$n10$$p2164 - 2185$$tAutophagy$$v20$$x1554-8627$$y2024
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