Abstract

ABSTRACTThe distinctive pathological hallmarks of Parkinson's disease are the progressive death of dopaminergic neurons and the intracellular accumulation of Lewy bodies enriched in α-synuclein protein. Several lines of evidence from the study of sporadic, familial and pharmacologically induced forms of human Parkinson's disease also suggest that mitochondrial dysfunction plays an important role in disease progression. Although many functions have been proposed for α-synuclein, emerging data from human and animal models of Parkinson's disease highlight a role for α-synuclein in the control of neuronal mitochondrial dynamics. Here, we review the α-synuclein structural, biophysical and biochemical properties that influence relevant mitochondrial dynamic processes such as fusion-fission, transport and clearance. Drawing on current evidence, we propose that α-synuclein contributes to the mitochondrial defects that are associated with the pathology of this common and progressive neurodegenerative disease.

Highlights

  • Parkinson’s disease (PD) is the second most common neurodegenerative disorder affecting humans, with a prevalence of around 0.3% among the worldwide population (Pringsheim et al, 2014)

  • The histopathology of PD is characterized by the presence in neurons of Lewy bodies, which are composed mainly of aggregates of the α-synuclein (α-Syn) protein (Lewy, 1912; Spillantini et al, 1998; Shults, 2006). (For an overview of the clinical features and current therapeutic strategies employed for PD, see Box 2.)

  • The gene coding for α-Syn, SNCA, was the first locus identified that linked genetics with PD (Polymeropoulos et al, 1997)

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Summary

Introduction

Parkinson’s disease (PD) is the second most common neurodegenerative disorder affecting humans, with a prevalence of around 0.3% among the worldwide population (Pringsheim et al, 2014). Different studies have linked the function of α-Syn to the maintenance of mitochondrial fusion-fission, transport and mitophagy (Box 1) (Choubey et al, 2011; Nakamura et al, 2011; O’Donnell et al, 2014; Zaichick et al, 2017) These processes, considered together as mitochondrial dynamics (Box 1), are extremely relevant in neurons owing to their high morphological polarization (reviewed extensively in Itoh et al, 2013; Mishra and Chan, 2016). A recent characterization of mitochondria in neurons from Caenorhabditis elegans revealed a mitochondria size increase during development, followed by a steady maintenance and a progressive decline of size and density during the organism’s lifespan (Morsci et al, 2016) These stages depend on fusion-fission proteins and on changes in mitochondrial transport and clearance, highlighting the influence of these processes in neuronal ageing, which is the main risk factor for PD (Collier et al, 2011; Niccoli and Partridge, 2012).

Mitophagy
Findings
C Mitophagy
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