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  • PMID: 27562021 was deleted because it is a duplicate of PMID: 28173004
Hum Mol Genet. 2016 Oct 15;25(20):4507-4517. doi: 10.1093/hmg/ddw279.

Impaired striatal dopamine release in homozygous Vps35 D620N knock-in mice.

Author information

1
Department of Neurology and Neurological Science, Tokyo Medical and Dental University Graduate School of Medical and Dental Sciences, Tokyo, Japan.
2
Department of Neurology, Tokyo National Hospital, Tokyo Japan
3
Department of Clinical research, Tokyo National Hospital, Tokyo Japan.
4
Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
5
Department of Neurobiology, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
6
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
7
Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, Japan.
8
National Center of Neurology and Psychiatry, Tokyo, Japan

Abstract

Point mutations in the vacuolar protein sorting 35 gene (VPS35) have been associated with an autosomal dominant form of late-onset Parkinson disease (PARK17), but there has been considerable debate over whether it is caused by a loss- or gain-of-function mechanism and over the intracellular target site of neurotoxicity. To investigate the pathogenesis of PARK17 in vivo, we generated Vps35 D620N knock-in (KI) mice, expressing the homologous mutant protein with endogenous patterns of expression, simultaneously with Vps35 deletion 1 (Del1) mice, which carry 1bp deletion in the exon15 of Vps35, by CRISPR/Cas9-mediated genome engineering. Neither homozygous nor heterozygous Vps35 D620N KI mice suffered from premature death or developed clear neurodegeneration up to 70 weeks of age. Vps35 Del1 allele appeared to be a null or at least severely hypomorphic allele and homozygous Vps35 Del1 showed early embryonic lethality. Heterozygous crossings between Del1 and D620N knock-in mice revealed that the D620N/Del1 compound heterozygous mice, but not heterozygous Del1 mice, suffered from survival disadvantage. In vivo microdialysis showed that DA release evoked by 120 mM potassium chloride was significantly reduced in the caudate putamen of adult homozygous Vps35 D620N KI mice. Taken together, these results suggest that Vps35 D620N allele is a partial-loss-of-function allele and that such a genetic predisposition and age-related alterations in the nigrostriatal dopamine system cooperatively influence the pathogenesis of PARK17.

PMID:
28173004
DOI:
10.1093/hmg/ddw279
[Indexed for MEDLINE]

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