Review
Mitochondrial dysfunction and mitophagy in Parkinson's: from familial to sporadic disease

https://doi.org/10.1016/j.tibs.2015.02.003Get rights and content

Highlights

  • A number of biochemical perturbations in Parkinson's disease (PD) are linked to mitochondrial dysfunction.

  • Progress in 2014 has defined new mechanisms of PINK1 and parkin-dependent mitophagy.

  • α-Synuclein (α-syn) levels and aggregation link mitochondria to familial and sporadic PD.

  • These new insights suggest novel mechanisms and therapeutic targets in PD.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterised by the preferential loss of dopaminergic neurons in the substantia nigra. Mitochondrial dysfunction is increasingly appreciated as a key determinant of dopaminergic neuronal susceptibility in PD and is a feature of both familial and sporadic disease, as well as in toxin-induced Parkinsonism. Recently, the mechanisms by which PD-associated mitochondrial proteins phosphatase and tensin homolog deleted on chromosome 10 (PTEN)-induced putative kinase 1 (PINK1) and parkin function and induce neurodegeneration have been identified. In addition, increasing evidence implicates other PD-associated proteins such as α-synuclein (α-syn) and leucine-rich repeat kinase 2 (LRRK2) in mitochondrial dysfunction in genetic cases of PD with the potential for a large functional overlap with sporadic disease. This review highlights how recent advances in understanding familial PD-associated proteins have identified novel mechanisms and therapeutic strategies for addressing mitochondrial dysfunction in PD.

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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