(D620N) VPS35 causes the impairment of Wnt/β-catenin signaling cascade and mitochondrial dysfunction in a PARK17 knockin mouse model

• Published in: Cell death & disease Vol. 11; no. 11; p. 1018
• Main Authors: Chiu, Ching-Chi, Weng, Yi-Hsin, Huang, Ying-Zu, Chen, Rou-Shayn, Liu, Yu-Chuan, Yeh, Tu-Hsueh, Lu, Chin-Song, Lin, Yan-Wei, Chen, Yu-Jie, Hsu, Chia-Chen, Chiu, Chi-Han, Wang, Yu-Ting, Chen, Wan-Shia, Liu, Shu-Yu, Wang, Hung-Li
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.11.2020; Springer Nature B.V
• Subjects: 13/2; 631/378/1934; 631/378/87; 64/60; 96/2; 96/95; Animal models; Animals; Antibodies; Basal ganglia; Biochemistry; Biomedical and Life Sciences; Caspase-3; Caspase-8; Caspase-9; Cell Biology; Cell Culture; Central nervous system diseases; Cytochrome c; Disease Models, Animal; Dopamine receptors; Electron transport chain; Humans; Hydroxylase; Immunology; Life Sciences; Mice; Middle Aged; Mitochondria; Mitochondria - metabolism; Morphology; Movement disorders; Mutation; NADH-ubiquinone oxidoreductase; Neurodegeneration; Neurodegenerative diseases; Oxidative stress; Parkinson Disease - genetics; Parkinson's disease; Protein transport; Proteins; Signal transduction; Substantia nigra; Survivin; Vesicular Transport Proteins - metabolism; Wnt Signaling Pathway - genetics
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-020-03228-9

Patients with familial type 17 of Parkinson’s disease (PARK17) manifest autosomal dominant pattern and late-onset parkinsonian syndromes. Heterozygous (D620N) mutation of vacuolar protein sorting 35 (VPS35) is genetic cause of PARK17. We prepared heterozygous VPS35 D620N/+ knockin mouse, which is an ideal animal model of (D620N) VPS35-induced autosomal dominant PARK17. Late-onset loss of substantia nigra pars compacta (SNpc) dopaminergic (DAergic) neurons and motor deficits of Parkinson’s disease were found in 16-month-old VPS35 D620N/+ mice. Normal function of VPS35-containing retromer is needed for activity of Wnt/β-catenin cascade, which participates in protection and survival of SNpc DAergic neurons. It was hypothesized that (D620N) VPS35 mutation causes the malfunction of VPS35 and resulting impaired activity of Wnt/β-catenin pathway. Protein levels of Wnt1 and nuclear β-catenin were reduced in SN of 16-month-old VPS35 D620N/+ knockin mice. Downregulated protein expression of survivin, which is a target gene of nuclear β-catenin, and upregulated protein levels of active caspase-8 and active caspase-9 were observed in SN of VPS35 D620N/+ mice at age of 16 months. VPS35 is involved in controlling morphology and function of mitochondria. Impaired function of VPS35 caused by (D620N) mutation could lead to abnormal morphology and malfunction of mitochondria. A significant decrease in mitochondrial size and resulting mitochondrial fragmentation was found in tyrosine hydroxylase-positive and neuromelanin-positive SNpc DAergic neurons of 16-month-old VPS35 D620N/+ mice. Mitochondrial complex I activity or complex IV activity was reduced in SN of 16-month-old VPS35 D620N/+ mice. Increased level of mitochondrial ROS and oxidative stress were found in SN of 16-month-old VPS35 D620N/+ mice. Levels of cytosolic cytochrome c and active caspase-3 were increased in SN of VPS35 D620N/+ mice aged 16 months. Our results suggest that PARK17 mutant (D620N) VPS35 impairs activity of Wnt/β-catenin signaling pathway and causes abnormal morphology and dysfunction of mitochondria, which could lead to neurodegeneration of SNpc DAergic cells.