ReviewProtein aggregation in the pathogenesis of familial and sporadic Parkinson's disease
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.
Section snippets
Intracellular protein clearance
Normal cellular functions are associated with the production of significant levels of abnormal proteins (i.e. incomplete, mutant, misfolded, denatured, oxidized and otherwise damaged proteins) [76], [208]. This is prominent in the CNS where the relatively high utilization of oxygen and elevated metabolic rate, and the enzymatic- and auto-oxidation of neurotransmitters such as dopamine, cause significant production of reactive oxygen species and other free radicals that can damage proteins [116]
Protein aggregation in Parkinson's disease
The primary pathology of PD is progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) [68]. However, prominent neurodegeneration also occurs in other areas, in particular the locus coeruleus, dorsal motor nucleus of the vagus, nucleus basalis of Meynert, olfactory system and peripheral autonomic nervous system [23], [68], [107], [237], [245]. Several lines of investigation have shown that neurodegeneration in the SNc and at various other pathological sites
The cause of protein aggregation and relationship to other changes in PD
The cause of protein accumulation and aggregation in PD appears to be multifactoral and may reflect the different etiologies or biochemical changes that occur in the different forms of the illness (Fig. 3). In some cases, protein accumulation and aggregation may occur early in the initiation of the neurodegenerative process, while in other cases these changes may arise as a consequence of primary biochemical alterations. Indeed, given that the UPS plays a key role in mediating cellular
Role of protein aggregation in the pathogenic process in PD
There is convincing evidence pointing to protein aggregation in the sporadic and various familial forms of PD. However, whether protein aggregation causes/contributes to neuronal death, is a cytoprotective response to other toxic factors, or is a benign occurrence in the pathogenic process, is unclear (Fig. 3).
The accumulation and aggregation of abnormal proteins can directly interfere with a variety of intracellular processes, alter cell viability and induce cytotoxicity [14], [33], [76], [208]
Therapeutic strategies based on interruption of protein aggregation in PD
The recognition that protein aggregation likely plays a role in the etiopathogenesis of PD provides novel targets for therapies that might interfere with the neurodegenerative process. It is thus reasonable to propose that inhibition of protein aggregation could modify the natural course of PD. This might be accomplished through the reduction of protein misfolding or stimulation of proteolysis using drug-based or gene therapy approaches. Recent laboratory studies have begun to address these
Conclusion
In recent years, several lines of research have provided corroborating and convincing evidence that protein aggregation plays a role in the pathogenic process occurring in sporadic and increasing numbers of familial forms of PD. Further, there appears to be a close relationship between protein aggregation and other defects found in PD, such as oxidative stress, mitochondrial inhibition, and proteasomal dysfunction. Indeed, it is possible that toxin-induced inhibition of proteolysis leading to
Acknowledgements
This study was supported by grants from the Bachmann-Strauss Dystonia & Parkinson Foundation Inc., the Bendheim Parkinson's Disease Center, the Morris and Alma Schapiro Foundation, and the NIH/NINDS (1 RO1 NS045999-01).
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