Diversity of Mitochondrial Pathology in a Mouse Model of Axonal Degeneration in Synucleinopathies

Akio Sekigawa,Masayo Fujita,Yoshiki Takamatsu,Kazunari Sekiyama,Takato Takenouchi,Masaaki Waragai,Makoto Hashimoto,Shuei Sugama

doi:10.1155/2013/817807

Abstract

There is mounting evidence for a role of mitochondrial dysfunction in the pathogenesis of α-synucleinopathies such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In particular, recent studies have demonstrated that failure of mitochondrial quality control caused by loss of function of the PTEN-induced kinase 1 (PINK1, PARK6) Parkin (PARK2) pathway may be causative in some familial PD. In sporadic PD, α-synuclein aggregation may interfere with mitochondrial function, and this might be further exacerbated by leucine-rich repeat kinase 2 (LRRK2). The majority of these findings have been obtained in Drosophila and cell cultures, whereas the objective of this paper is to discuss our recent results on the axonal pathology of brains derived from transgenic mice expressing α-synuclein or DLB-linked P123H β-synuclein. In line with the current view of the pathogenesis of sporadic PD, mitochondria abnormally accumulated in α-synuclein/LRRK2-immunopositive axonal swellings in mice expressing α-synuclein. Curiously, neither mitochondria nor LRRK2 was present in the swellings of mice expressing P123H β-synuclein, suggesting that α- and β-synuclein might play differential roles in the mitochondrial pathology of α-synucleinopathies.

Highlights

The high energy consumption in neural activities in brains makes mitochondria important in neurons as regulators of energy metabolism, the NAD+/NADH ratio, and endogenous production of reactive oxygen species
PINK1 is rapidly degraded in healthy mitochondria but accumulates in membrane potential (ΔΨm) deficient mitochondria, where it recruits Parkin to ubiquitinate the damaged mitochondria, which leads to fission and processing for degradation in the lysosome; this mechanism is referred to as “mitophagy.” a prevalent view regarding the pathogenesis of some types of Parkinson’s disease (PD) (Figure 1) is that PINK1 acts upstream of Parkin in a common pathway that appears to regulate mitochondrial quality and morphology and that dysregulation of the PINK1/Parkin pathway may result in a failure to remove damaged mitochondria, leading to enhanced oxidative stress conditions
The results of our studies in tg mice provide novel information showing that αS-globules derived from αS tg mice and P123H βS-globules derived from P123H βS tg mice have similar but distinct characteristics

Summary

Introduction

The high energy consumption in neural activities in brains makes mitochondria important in neurons as regulators of energy metabolism (as ATP producers), the NAD+/NADH ratio, and endogenous production of reactive oxygen species (reviewed in [1]). High levels of mtDNA deletions have been observed in dopaminergic neurons from the substantia nigra of postmortem human brains from elderly individuals and idiopathic PD patients [6] Besides this circumstantial evidence, recent genetic studies of PD risk factors have unambiguously shown the central role of mitochondria in the pathogenesis of PD [7]. PINK1 is rapidly degraded in healthy mitochondria but accumulates in membrane potential (ΔΨm) deficient mitochondria, where it recruits Parkin to ubiquitinate the damaged mitochondria, which leads to fission and processing for degradation in the lysosome; this mechanism is referred to as “mitophagy.” a prevalent view regarding the pathogenesis of some types of PD (Figure 1) is that PINK1 acts upstream of Parkin in a common pathway that appears to regulate mitochondrial quality and morphology and that dysregulation of the PINK1/Parkin pathway may result in a failure to remove damaged mitochondria, leading to enhanced oxidative stress conditions These conditions may lead to secondary induction of aggregation of αS [14]

Role of α-Synuclein and LRRK2 in the Mitochondrial Pathology of Sporadic PD

Summary and Perspective: A Heterogeneity Problem?