title: Pathogenic mutation in VPS35 impairs its protection against MPP(+) cytotoxicity.
abstract: Parkinson's disease primarily results from progressive degeneration of dopaminergic neurons in the substantia nigra. Both neuronal toxicants and genetic factors are suggested to be involved in the disease pathogenesis. The mitochondrial toxicant 1-methyl-4-phenylpyridinium (MPP(+)) shows a highly selective toxicity to dopaminergic neurons. Recent studies indicate that mutation in the vacuolar protein sorting 35 (vps35) gene segregates with Parkinson's disease in some families, but how mutation in the vps35 gene causes dopaminergic cell death is not known. Here, we report that enhanced VPS35 expression protected dopaminergic cells against MPP(+) toxicity and that this neuroprotection was compromised by pathogenic mutation in the gene. A loss of neuroprotective functions contributes to the pathogenesis of VPS35 mutation in Parkinson's disease.
authors: Department of Neurology, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107, USA.
authors: Fangfang
authors: F
authors: Bi
authors: Fang
authors: F
authors: Li
authors: Cao
authors: C
authors: Huang
authors: Hongxia
authors: H
authors: Zhou
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D003001:Cloning, Molecular; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000235:genetics*; D005822:Genetic Vectors; D006801:Humans; D015151:Immunoblotting; D008856:Microscopy, Fluorescence; D016296:Mutagenesis; D020125:Mutation, Missense / Q000235:genetics; D016366:Open Reading Frames / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics*; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C419573:VPS35 protein, human; D033921:Vesicular Transport Proteins; D015655:1-Methyl-4-phenylpyridinium
keywords: 1-methyl-4-phenylpyridinium; MPP; Parkinson's disease; VPS35; vacuolar protein sorting 35