Trends in Biochemical Sciences
ReviewMitochondrial dysfunction and mitophagy in Parkinson's: from familial to sporadic disease
Section snippets
Mitochondrial dysfunction in PD
PD is the second most common neurodegenerative disease affecting 1% of the population over the age of 60. The cardinal motor symptoms of PD are a result of the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc; see Glossary) causing a deficiency of dopamine in the striatum. The exact aetiology and natural course of the disease has yet to be fully characterised but involves dysfunction of numerous systems-level processes including mitochondrial function, calcium
PINK1, parkin, and DJ-1 as key mediators of mitochondrial homeostasis and mitophagy
PINK1-dependent activation of parkin is recognised as a major route of mitophagy and is essential for mitochondrial quality control in a number of models; failure of this process results in the persistence of damaged, reactive oxygen species (ROS)-producing, mitochondria, resulting in cellular stress. Recently, significant advances have been made in defining the precise mechanism of PINK1-dependent parkin activation (Box 3). PINK1 activity is primarily regulated by mitochondrial import across
Roles of α-syn aggregation in mitochondrial dysfunction
The aggregation of α-syn and its incorporation as a major component of Lewy bodies is the hallmark of Parkinson's disease. Oligomerisation/aggregation of α-syn in response to oxidation or phosphorylation likely mediates its deleterious effects. Highly penetrant familial mutations or multiplications in the α-syn gene (SNCA) have been shown to cause aggressive early-onset PD. Additionally, a common SNP in the SNCA gene that is enriched in PD patients has been demonstrated to increase expression
The role of increased LRRK2 kinase activity in mitochondrial dysfunction
LRRK 2 is a multifunction protein with important kinase activities; the PD-associated mutation G2019S (kinase domain) is thought to increase kinase activity of the protein [47]. Wild type LRRK2 interacts with a number of key regulators of mitochondrial fission/fusion, co-localising with them either in the cytosol or on mitochondrial membranes, indicating it has multiple regulatory roles (Figure 2) 48, 49. It has been established that in murine primary neurons and human neuroblastoma, endogenous
Novel mitochondrial therapeutic targets
Models of autosomal dominant and autosomal recessive forms of PD demonstrate markedly different mechanisms for the induction of mitochondrial dysfunction and cellular stress. However, the outcomes of this dysfunction – increased ROS production and bioenergetic stress – are common to all forms of mitochondrial dysfunction (Box 1). The wealth of mechanistic information on the mitochondrial functions of PD-related proteins has identified a wide range of points for therapeutic intervention.
Concluding remarks
PD patients with either autosomal dominant or autosomal recessive PD, or models of these mutations, demonstrate mitochondrial complex-I deficiencies, mitochondrial DNA (mtDNA) damage, and oxidative stress. However, as discussed earlier, it is likely that mitochondrial dysfunction in autosomal dominant and autosomal recessive PD does not occur by the same mechanism. Indeed, even from a clinical perspective, autosomal recessive mutations may represent a nigral-specific degeneration (nigropathy)
Acknowledgements
The authors acknowledge funding support from the Monument Discovery Award from Parkinson's UK and Parkinson's UK grants G-0801 and G-1003. E.A.F. is supported by the Canadian Institutes of Health Research (CIHR) and a National Scholar Award from the Fonds de Recherche du Québec Santé (FRSQ).
Glossary
- Autophagy
- a process of degradation of cellular components via breakdown in the lysosome, either by direct import, that is, chaperone mediated autophagy (CMA), or by incorporation into autophagosomes and subsequent lysosomal fusion, that is, micro/macroautophagy.
- GWAS
- genome-wide association studies are used to identify SNPs, which are commonly present in the population, that are associated with a phenotype, for example, an increased risk of developing PD. GWAS can be used as a way of identifying
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