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@ARTICLE{deCalbiac:272348,
      author       = {de Calbiac, Hortense and Renault, Solène and Haouy,
                      Grégoire and Jung, Vincent and Roger, Kevin and Zhou, Qihui
                      and Campanari, Maria-Letizia and Chentout, Loïc and Demy,
                      Doris Lou and Marian, Anca and Goudin, Nicolas and Edbauer,
                      Dieter and Guerrera, Chiara and Ciura, Sorana and Kabashi,
                      Edor},
      title        = {{P}oly-{GP} accumulation due to {C}9orf72 loss of function
                      induces motor neuron apoptosis through autophagy and
                      mitophagy defects.},
      journal      = {Autophagy},
      volume       = {20},
      number       = {10},
      issn         = {1554-8627},
      address      = {Abingdon, Oxon},
      publisher    = {Taylor $\&$ Francis},
      reportid     = {DZNE-2024-01165},
      pages        = {2164 - 2185},
      year         = {2024},
      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.},
      keywords     = {Motor Neurons: metabolism / Motor Neurons: pathology /
                      Animals / C9orf72 Protein: genetics / C9orf72 Protein:
                      metabolism / Zebrafish / Mitophagy: genetics / Apoptosis:
                      genetics / Humans / Autophagy: genetics / Autophagy:
                      physiology / Amyotrophic Lateral Sclerosis: metabolism /
                      Amyotrophic Lateral Sclerosis: pathology / Amyotrophic
                      Lateral Sclerosis: genetics / Dipeptides: pharmacology /
                      Dipeptides: metabolism / Loss of Function Mutation: genetics
                      / Mitochondria: metabolism / Disease Models, Animal /
                      Amyotrophic lateral sclerosis (Other) / apoptosis (Other) /
                      mitochondria (Other) / motor neuron (Other) /
                      neurodegeneration (Other) / poly-GP (Other) / C9orf72
                      Protein (NLM Chemicals) / Dipeptides (NLM Chemicals)},
      cin          = {AG Zhou / AG Edbauer},
      ddc          = {570},
      cid          = {I:(DE-2719)5000080 / I:(DE-2719)1110004},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC11423671},
      pubmed       = {pmid:39316747},
      doi          = {10.1080/15548627.2024.2358736},
      url          = {https://pub.dzne.de/record/272348},
}