PINK1 Primes Parkin-Mediated Ubiquitination of PARIS in Dopaminergic Neuronal Survival
| Autor: | Fabienne C. Fiesel, Daniel A. Stevens, Stewart Neifert, Ted M. Dawson, Kathleen Allen, Hojin Kang, Sung Ung Kang, Joo Ho Shin, Leslie A. Scarffe, Yun Il Lee, Haisong Jiang, George Essien Umanah, Wolfdieter Springer, Saurav Brahmachari, Valina L. Dawson, Seung Pil Yun, Tae In Kam, Yunjong Lee, Sangwoo Ham, Jungwoo Wren Kim, Han Seok Ko |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Parkinson's disease PGC-1α Parkin Mice 0302 clinical medicine Ubiquitin parkin Phosphorylation RNA Small Interfering Promoter Regions Genetic lcsh:QH301-705.5 Genetics biology Dopaminergic ZNF746 Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Cell biology RNA Interference medicine.drug Chromatin Immunoprecipitation Ubiquitin-Protein Ligases Mice Transgenic PINK1 Substantia nigra Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Dopamine Cell Line Tumor medicine Animals Humans Psychological repression Dopaminergic Neurons Ubiquitination medicine.disease nervous system diseases Mice Inbred C57BL Repressor Proteins 030104 developmental biology lcsh:Biology (General) PARIS Proteolysis Parkinson’s disease Mutagenesis Site-Directed biology.protein Protein Kinases 030217 neurology & neurosurgery |
| Zdroj: | Cell Reports, Vol 18, Iss 4, Pp 918-932 (2017) |
| ISSN: | 2211-1247 |
| Popis: | Mutations in PTEN-induced putative kinase 1 (PINK1) and parkin cause autosomal-recessive Parkinson’s disease through a common pathway involving mitochondrial quality control. Parkin inactivation leads to accumulation of the parkin interacting substrate (PARIS, ZNF746) that plays an important role in dopamine cell loss through repression of proliferator-activated receptor gamma coactivator-1-alpha (PGC-1α) promoter activity. Here, we show that PARIS links PINK1 and parkin in a common pathway that regulates dopaminergic neuron survival. PINK1 interacts with and phosphorylates serines 322 and 613 of PARIS to control its ubiquitination and clearance by parkin. PINK1 phosphorylation of PARIS alleviates PARIS toxicity, as well as repression of PGC-1α promoter activity. Conditional knockdown of PINK1 in adult mouse brains leads to a progressive loss of dopaminergic neurons in the substantia nigra that is dependent on PARIS. Altogether, these results uncover a function of PINK1 to direct parkin-PARIS-regulated PGC-1α expression and dopaminergic neuronal survival. |
| Databáze: | OpenAIRE |
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