Loss of Parkin contributes to mitochondrial turnover and dopaminergic neuronal loss in aged mice

NEUROBIOLOGY OF DISEASE

卷:136

Article

Noda, Sachiko¹  Sato, Shigeto¹  Fukuda, Takahiro²  Tada, Norihiro³  Uchiyama, Yasuo⁴  Tanaka, Keiji⁵  Hattori, Nobutaka¹ 

[1] Juntendo Univ, Dept Neurol, Grad Sch Med, Tokyo 1138421, Japan

[2] Jikei Univ, Sch Med, Dept Neuropathol, Div Neuropathol, Tokyo 1058461, Japan

[3] Juntendo Univ, Atopy Res Ctr, Sch Med, Tokyo 1138421, Japan

[4] Juntendo Univ, Dept Cellular & Mol Neuropathol, Grad Sch Med, Tokyo 1138421, Japan

[5] Metropolitan Inst Med Sci, Lab Prot Metab, Tokyo, Japan

关键词: Parkinson's disease;    Parkin;    Mitochondria;    Dopaminergic neuron;    Aging;   

DOI  :  10.1016/j.nbd.2019.104717

来源: Elsevier

【 摘 要 】

Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by the loss of nigrostriatal dopamine neurons. PARK2 mutations cause early-onset Parkinson's disease (EO-PD). PARK2 encodes an E3 ubiquitin ligase, Parkin. Extensive in vitro studies and cell line characterization have shown that Parkin is required for mitophagy, but the physiological pathology and context of the pathway remain unknown. In general, monogenic Parkin knockout mice do not accurately reflect human PD symptoms and exhibit no signs of dopaminergic (DA) neurodegeneration. To assess the critical role of Parkin-mediated mitophagy in DA neurons, we characterized Parkin knockout mice over a long period of time. At the age of 110 weeks, Parkin knockout mice exhibited locomotor impairments, including hindlimb defects and neuronal loss. In their DA neurons, fragmented mitochondria with abnormal internal structures accumulated. The age-related motor dysfunction and damaged mitochondria pathology in Parkin-deficient mice suggest that impairment of mitochondria! clearance may underlie the pathology of PD.