(G308D) PINK1 knockin mice exhibit the death of substantia nigra dopaminergic neurons and motor deficits

• Main Authors: Ya Ming Chang, 張亞明
• Other Authors: H. L. Wang
• Format: Others
• Language: en_US
• Published: 2017
• Online Access: http://ndltd.ncl.edu.tw/handle/986p77

碩士 === 長庚大學 === 生物醫學研究所 === 106 === Parkinson’s disease (PD) is the most common neurodegenerative motor disorder. Current treatment for PD is symptomatic, and there is no disease-modifying treatment that could halt or delay disease progression. Recent studies demonstrated that homozygous missense or truncating mutations of PTEN-induced kinase 1 (PINK1) gene are implicated in the pathogenesis of PARK6 and that PINK1 is the second most frequent causative gene in early-onset PD. PINK1 is believed to regulate mitochondrial functions of SNpc dopaminergic neurons and exert neuroprotective effect against various cellular stresses by functioning as a mitochondrial Ser/Thr protein kinase. The loss-of-function PARK6 mutations result in degeneration of neurons and parkinsonism. Moreover, clinical features exhibited by PINK1-mutation carriers are indistinguishable from those observed in sporadic PD patients. Thus investigating PARK6 mutant PINK1-induced parkinsonism is important to unveil the common pathogenic mechanism of PARK6 and sporadic PD and could lead to the development of possible therapeutic strategies for both PARK6 and sporadic PD. In present studies, we established knockin mice expressing PARK6 mutant (G308D) PINK1.Similar to PD patients with (G309D) PINK1 mutation, PINK1G308D/G308D knockin mice at the ages of 12-16 months exhibited progressive degeneration of SNpc dopaminergic neurons and parkinsonism phenotypes of motor dysfunction.In contrast, knockin mice expressing (G308D) PINK1 did not display neuronal death of striatum and cerebral cortex.18F-FP-DTBZ microPET study also indicated that (G308D) PINK1 caused the damage of nigrostriatal dopaminergic terminals in (G308D) PINK1 homozygous knockin mice. Proteomic identification of substrates of mutant (G309D) PINK1-mediated phosphorylation in vivo were employed to understand the molecular mechanism of mutant PINK1-induced neurodegeneration of nigrostriatal system and resultant parkinsonism. Our phosphoproteomic analysis using liquid chromatography (LC)-mass spectrometry (MS) indicated that putative phosphorylated substrates of PINK1 in the substantia nigra were involved in regulating mitochondria-mediated apoptosis, mitochondrial metabolic function, neuronal survival, ER stress response, various signal pathways, ubiquitin-proteasome system and axon/dendritic development. The present study using knockin animal model should shed light on the common pathogenic mechanism of PARK6 and sporadic PD and physiological functions of PINK1 in the brain. The results obtained from the in vivo models for PD could also lead to the development of possible therapeutic strategies for PD.