Genetic Mutations and Mitochondrial Toxins Shed New Light on the Pathogenesis of Parkinson's Disease

Shigeto Sato,Nobutaka Hattori

doi:10.4061/2011/979231

Shigeto Sato, Nobutaka Hattori

Open Access

https://doi.org/10.4061/2011/979231

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Journal: Parkinson's disease	Publication Date: Jan 1, 2011
Citations: 71	License type: CC BY 3.0

Affiliation: Juntendo University

Abstract

The cellular abnormalities in Parkinson's disease (PD) include mitochondrial dysfunction and oxidative damage, which are probably induced by both genetic predisposition and environmental factors. Mitochondrial dysfunction has long been implicated in the pathogenesis of PD. The recent discovery of genes associated with the etiology of familial PD has emphasized the role of mitochondrial dysfunction in PD. The discovery and increasing knowledge of the function of PINK1 and parkin, which are associated with the mitochondria, have also enhanced the understanding of cellular functions. The PINK1-parkin pathway is associated with quality control of the mitochondria, as determined in cultured cells treated with the mitochondrial uncoupler carbonyl cyanide m-chlorophenylhydrazone (CCCP), which causes mitochondrial depolarization. To date, the use of mitochondrial toxins, for example, 1-methyl-4-phynyl-tetrahydropyridine (MPTP) and CCCP, has contributed to our understanding of PD. We review how these toxins and familial PD gene products are associated with and have enhanced our understanding of the role of mitochondrial dysfunction in PD.

Highlights

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, affecting 1% of the population above the age of 60
The active metabolite of MPTP, 1-methyl-4-phenylpyridinium ion (MPP+), is an inhibitor of complex I, and it accumulates in dopaminergic neurons because it is actively transported via dopamine transporter (DAT) [4,5,6]
PINK1 loss-of-function results in reduced mitochondrial membrane potential [52], and the PINK1-parkin pathway is associated with mitochondrial elimination in cultured cells treated with the mitochondrial uncoupler carbonyl cyanide m-chlorophenylhydrazone (CCCP), which causes mitochondrial depolarization [53,54,55,56,57,58]

Summary

Introduction

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, affecting 1% of the population above the age of 60. There was dissociation in the resistance between MPTP- and rotenoneinduced cell vulnerability of synuclein-null dopaminergic neurons [24] This result suggests that MPTP associates with synuclein through another pathway independent of complex I inhibition (mitochondrial dysfunction), to induce dopaminergic cell death. Many mutations of the parkin gene at the PARK2 locus induce autosomal recessive Parkinsonism [34,35,36,37,38]. PINK1 loss-of-function results in reduced mitochondrial membrane potential [52], and the PINK1-parkin pathway is associated with mitochondrial elimination in cultured cells treated with the mitochondrial uncoupler carbonyl cyanide m-chlorophenylhydrazone (CCCP), which causes mitochondrial depolarization [53,54,55,56,57,58]. While CCCP is well described, its mitochondrial toxic effects provide new insights on the functional interplay between PINK1 and parkin

Accumulation of PINK1 in Damaged Mitochondria

PINK1 Kinase Activity Is Essential for Translocation of Parkin

PINK1 Deficiency Itself Causes Respiratory Chain Defects

Findings

Conclusion