title: PINK1 and Parkin cooperatively protect neurons against constitutively active TRP channel-induced retinal degeneration in Drosophila.
abstract: Calcium has an important role in regulating numerous cellular activities. However, extremely high levels of intracellular calcium can lead to neurotoxicity, a process commonly associated with degenerative diseases. Despite the clear role of calcium cytotoxicity in mediating neuronal cell death in this context, the pathological mechanisms remain controversial. We used a well-established Drosophila model of retinal degeneration, which involves the constitutively active TRP(P365) channels, to study calcium-induced neurotoxicity. We found that the disruption of mitochondrial function was associated with the degenerative process. Further, increasing autophagy flux prevented cell death in Trp(P365) mutant flies, and this depended on the PINK1/Parkin pathway. In addition, the retinal degeneration process was also suppressed by the coexpression of PINK1 and Parkin. Our results provide genetic evidence that mitochondrial dysfunction has a key role in the pathology of cellular calcium neurotoxicity. In addition, the results demonstrated that maintaining mitochondrial homeostasis via PINK1/Parkin-dependent mitochondrial quality control can potentially alleviate cell death in a wide range of neurodegenerative diseases.
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.|National Institute of Biological Sciences, Beijing, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Huang
authors.affiliation: National Institute of Biological Sciences, Beijing, China.|College of Biological Sciences, China Agricultural University, Beijing, China.
authors.forename: S
authors.initials: S
authors.lastname: Ren
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: National Institute of Biological Sciences, Beijing, China.
authors.forename: T
authors.initials: T
authors.lastname: Wang
mesh_terms: D000818:Animals; D017920:Antiporters / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D000071189:Autophagy-Related Protein-1 Homolog / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism / Q000633:toxicity; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004330:Drosophila / Q000235:genetics* / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000378:metabolism; D063154:Mitochondrial Dynamics; D016296:Mutagenesis; D009474:Neurons / Q000378:metabolism; D010786:Photoreceptor Cells / Q000166:cytology / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012162:Retinal Degeneration / Q000378:metabolism / Q000473:pathology*; D012243:Rhodopsin / Q000235:genetics; D050051:Transient Receptor Potential Channels / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D017920:Antiporters; D000071189:Autophagy-Related Protein-1 Homolog; D002118:Calcium; D002135:Calcium-Binding Proteins; D029721:Drosophila Proteins; D017346:Protein Serine-Threonine Kinases; D012243:Rhodopsin; D050051:Transient Receptor Potential Channels; D044767:Ubiquitin-Protein Ligases; C544264:Letm1 protein, Drosophila; C083315:ninaE protein, Drosophila; C063169:trp protein, Drosophila; C518074:Atg1 protein, Drosophila; C534484:PINK1 protein, Drosophila; D000099202:PTEN-Induced Putative Kinase; C487430:park protein, Drosophila