PINK1 Primes Parkin-Mediated Ubiquitination of PARIS in Dopaminergic Neuronal Survival.
PINK1 Primes Parkin-Mediated Ubiquitination of PARIS in Dopaminergic Neuronal Survival.
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DOI：
10.1016/j.celrep.2016.12.090
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发表时间：
2017-01-24
期刊：
影响因子：
8.8
通讯作者：
Dawson TM
中科院分区：
文献类型：
--
作者：
Lee Y;Stevens DA;Kang SU;Jiang H;Lee YI;Ko HS;Scarffe LA;Umanah GE;Kang H;Ham S;Kam TI;Allen K;Brahmachari S;Kim JW;Neifert S;Yun SP;Fiesel FC;Springer W;Dawson VL;Shin JH;Dawson TM
PTEN诱导的推定激酶1（PINK 1）和parkin突变通过涉及线粒体质量控制的共同途径引起常染色体隐性帕金森病。帕金失活导致帕金相互作用底物（巴黎，ZNF 746）蓄积，该底物通过抑制增殖物激活受体γ共激活因子-1 α（PGC-1α）启动子活性在多巴胺细胞丢失中起重要作用。在这里，我们表明，巴黎，链接PINK 1和parkin在一个共同的途径，调节多巴胺能神经元的生存。PINK 1与巴黎的丝氨酸322和613相互作用并磷酸化，以控制其泛素化和被parkin清除。巴黎的PINK 1磷酸化增强了巴黎的毒性以及PGC-1α启动子活性的抑制。PINK 1在成年小鼠脑中的条件性敲除导致黑质中依赖于巴黎的多巴胺能神经元的进行性丧失。总之，这些结果揭示了PINK 1指导parkin-PARIS调节的PGC-1α表达和多巴胺能神经元存活的功能。Lee等人证明巴黎是PINK 1和parkin的共同底物。巴黎的PINK 1磷酸化使其开始泛素化并被parkin清除。因此，PINK 1或parkin的功能障碍汇聚到巴黎积累上，这导致PGC-1α抑制和多巴胺神经元损失。
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-1α (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. Together, these results uncover a function of PINK1 to direct parkin-PARIS regulated PGC-1α expression and dopaminergic neuronal survival. Lee et al. demonstrate that PARIS is a common substrate of PINK1 and parkin. PINK1 phosphorylation of PARIS primes it for ubiquitination and clearance by parkin. Thus, dysfunction of either PINK1 or parkin converges onto PARIS accumulation, which leads to PGC-1α repression and dopamine neuron loss.