Trends in Neurosciences
Reviewα-Synuclein and dopamine at the crossroads of Parkinson's disease
Introduction
PD is a progressive and devastating neurodegenerative disorder, affecting 1% of individuals over 60 years old [1]. The three cardinal clinical features of PD are rigidity, resting tremor and bradykinesia, and these occur when approximately 50% of dopaminergic neurons projecting from the substantia nigra pars compacta (SNc) to the striatum are lost [1]. The neuropathological hallmark of the disease is the presence in surviving SNc neurons of intracellular inclusions known as Lewy bodies (LBs), which are composed mainly of the protein α-synuclein (Box 1) 1, 2. The pathology of PD is not solely confined to the nigrostriatal pathway because LBs are also found in the cortex, amygdala, locus coeruleus and peripheral autonomic system 3, 4. Dysfunction of these extranigral neuronal populations and the presence of LBs correlate with the non-motor manifestations of PD, including autonomic, sleep and olfactory dysfunctions, and these can precede the appearance of motor symptoms 3, 4. Although there is increasing awareness of the importance of these non-motor symptoms, the nigrostriatal dopaminergic pathway remains a focus for research and therapeutic intervention in treating the debilitating motor symptoms of PD.
PD is an excellent example of a neurological disorder in which a complex mix of aging, genetic susceptibility and environmental insult converge to varying degrees along a spectrum to cause neurodegeneration and disease. At the extreme genetic end of the spectrum is familial PD caused by mutations in one of twelve known loci that together constitute 10% of PD cases [5]. At the extreme environmental-exposure end are a few cases of PD associated with the potent neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [6]. However, it is likely that the majority of sporadic PD cases result from a complex interaction between genes and environment, played out against the background of age, which remains the greatest risk factor. A multiple-hit hypothesis has recently been proposed for dopaminergic neuron loss in PD [7], suggesting the preferential neuronal death results from a combination of toxic cellular insults, from mitochondrial dysfunction or dopamine oxidation, and an impaired stress-induced protective response. Here we discuss the latest research on the contribution of α-synuclein to dopaminergic neurodegeneration in PD, bringing together recent genetic evidence supporting the involvement of α-synuclein gene variants in PD etiology with key findings emphasizing the role of α-synuclein in regulating dopamine metabolism and neurotransmission.
Section snippets
The α-synuclein gene plays a role in both familial and sporadic PD
The first genetic evidence for the involvement of the α-synuclein gene, SNCA, in PD was the identification of three missense mutations (A30P, E46K and A53T) which segregated with the disease in unrelated families and caused PD with high penetrance 8, 9, 10. Duplications and triplications of the wild-type SNCA locus have also been associated with autosomal dominant PD 11, 12, 13, 14. The presence of multiple copies of the gene was directly correlated with an increase in α-synuclein mRNA
Potential SNCA-associated disease mechanisms
The likely impact of disease-associated SNCA variants identified by GWAS 16, 17, 20 includes altered control of the level of transcription, regulation of alternative splicing, or altered stability of mRNA through post-transcriptional mechanisms (Figure 1).
α-Synuclein regulates the key stages of dopamine homeostasis
Although α-synuclein is widely expressed in the brain, PD-associated degeneration occurs preferentially in specific regions of the CNS, with the major pathology and the greatest loss of cells in the SNc leading to the principal motor symptoms. Understanding exactly how the regulation of dopamine homeostasis is affected by genetic variation at the α-synuclein locus is a major question in PD which remains to be answered.
Unique properties of dopaminergic neurons account for preferential neurodegeneration
Mesostriatal dopaminergic neurons have several properties that could be factors in their susceptibility to neurodegeneration. Single nigrostriatal dopamine neurons in the rat brain have been shown to have a total cumulative axonal length as great as 70 cm [67], and it has been estimated that these axons could form 200 000–400 000 release sites or synapses in the striatum 68, 69. Thus, dopaminergic neurons have extraordinary high metabolic demands and turnover, which might in turn help to explain
α-Synuclein dysfunction tips dopaminergic neurons over the edge
If one were to extrapolate the results obtained in primary neuronal cultures to native neurons in the brain, it is possible that the preferential vulnerability of a subgroup of dopaminergic neurons in the SNc arises from the convergence of different cellular risk factors, in particular the interaction between increased cytosolic dopamine concentrations and α-synuclein expression (Figure 4). High cytoplasmic calcium levels are likely to lead to increased cytosolic dopamine concentrations in
Concluding remarks and future directions
Recent evidence from large GWAS involving many thousands of PD patients, together with new experimental data on dopamine cellular physiology, point to α-synuclein as a key link between familial and sporadic PD, and as a crucial regulator of dopamine homeostasis. A number of key questions remain to be answered (Box 2), including two main challenges. First, to further dissect the important roles that α-synuclein plays in regulating dopaminergic neurotransmission and in defining the unique
Acknowledgements
We thank Parkinson's UK, The Monument Trust Discovery Award and the Wellcome Trust for supporting our work. L.L.V. is funded by Fundação para a Ciência e Tecnologia, Portugal.
Glossary
- Genome-wide association studies (GWAS)
- a powerful approach to identify common genetic variants of weak effect that underlie the risk of common disease. A GWAS is a case–control genetic association study scanning across the entire genome using densely distributed genetic markers to compare genetic variation between affected and unaffected individuals. Stringent statistical correction procedures, such as the Bonferroni correction for multiple testing, are generally adopted when analyzing the GWAS
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