Protein aggregation in the pathogenesis of familial and sporadic Parkinson's disease

Abstract

Parkinson's disease (PD) is a slowly progressive, age-related, neurodegenerative disorder. The cause and mechanism of neuronal death have been elusive. However, recent genetic, postmortem and experimental evidence show that protein accumulation and aggregation are prominent occurrences in both sporadic and familial PD. The relevance of these events to other cellular and biochemical changes, and to the neurodegenerative process, is being unraveled. It is increasingly evident that one or a combination of defects, including mutations, oxidative stress, mitochondrial impairment and dysfunction of the ubiquitin–proteasome system, lead to an excess production and aggregation of abnormal proteins in PD. In this respect, altered protein handling appears to be a central factor in the pathogenic process occurring in the various hereditary and sporadic forms of PD. This suggests that manipulation of proteolytic systems is a rational approach in the development of neuroprotective therapies that could modify the pathological course of PD.

Introduction

Parkinson's disease (PD) is the second most common neurodegenerative disorder, after Alzheimer's disease [128], [129], [145]. The incidence and prevalence rates of PD increase with ageing, affecting approximately 0.3% of the general population and rises to 1–2% of individuals who are ≥65 years old (which is the mean age of disease onset) [47], [144], [234]. Thus, as life expectancy of the general population continues to rise, the occurrence of PD is also likely to increase. These trends underscore the need for the development of effective therapies for the illness. PD is slowly progressive and is characterized clinically by bradykinesia, rigidity, postural instability and gait dysfunction. The symptoms of the disorder are readily controlled with dopaminergic therapy in the early stages [203]. However, in the advanced stages of the disease, such benefits are limited due to the development of treatment-related motor complications (e.g. motor fluctuations and dyskinesias), onset of psychiatric disturbances, and the occurrence of features (e.g. autonomic dysfunction, freezing episodes and dementia) that are not adequately controlled with available therapies [203]. These problems can represent a major source of disability to PD patients, and likely reflect the continuing expansion and progression of the neurodegenerative process. Thus, there is an urgent need to develop neuroprotective therapies that can slow or halt progression of the pathogenic course in PD. The achievement of this goal would be facilitated by deciphering the factors which underlie the initiation, development or progression of the neurodegenerative process in PD.

The pathogenesis of PD has been linked to a variety of cellular, biochemical and molecular alterations. Oxidative stress likely occurs in the SNc in PD [108] based on findings of reduced levels of the anti-oxidant reduced glutathione (GSH) [212], increase levels of the pro-oxidant iron [49], [91], [218], and evidence of oxidative damage to proteins, lipids and DNA [3], [50], [51], [247]. Mitochondrial dysfunction, as evidenced by reduced activity and decreased staining for complex I, may also be an important factor [182], [202]. The appearance of activated microglia [146] and increased cytokine levels [19], [96], [163], [164], [165], suggest the occurrence of an inflammatory response that is potentially deleterious [97], [147]. There is also evidence for cell damage secondary to glutamate/nitric oxide (NO)-mediated excitotoxicity [11], [46], [80]. Finally, activation of pro-apoptotic and autophagic pathways have been implicated in PD [5], [92], [226], [227]. More recently, several lines of genetic, postmortem and experimental evidence show that protein aggregation is closely associated with the pathogenic process in familial and sporadic forms of PD [87], [153], [167], [178].

There are several recent and excellent reviews focusing on the role of α-synuclein in α-synucleinopathies including PD [178]. In this review, we will consider the role that protein aggregation plays in the various familial and sporadic forms of PD. We begin with a brief coverage of the systems involved in intracellular protein clearance and aggregation; and then discuss how these mechanisms are altered and their possible relationship to other cellular/biochemical changes and the neurodegenerative process that occur in PD. We conclude by proposing targets in the protein handling systems that might be exploited to develop neuroprotective therapies for the illness.