Introduction
Parkinson’s disease (PD) is a neurodegenerative condition that has a myriad of manifestations in the motor and non motor systems. Motor manifestations result from loss of dopaminergic neurons that occur in the nigrostriatal system. Symptoms of PD manifest when there is loss of more than half of the dopaminergic neurons. These include bradykinesia, stiffness and tremors at rest. The main neurons affected are those originating from the substantia nigra pars compacta (SNc). These neurons have the Lewy bodies as their main component. Lewy bodies are mainly composed of a special protein called α-synuclein that scientists believe is core to the neuropathology of PD. In this review, we highlight recent findings of the involvement of α-synuclein in degeneration of dopaminergic neurons in PD (Venda, Cragg, Buchman & Wade-Martins, 2010).
The Role of α-Synuclein Gene in Familial and Sporadic PD
Mutations in the α-synuclein gene (SNCA) have been shown to precipitate PD. Studies have shown a linear correlation between the extent of over expression of SCNA and the rigorousness of both familial and sporadic PD. In addition, the progression of the degenerative process had a similar linear relationship, reinforcing the involvement of SCNA in PD.
SNCA-associated disease mechanisms
Various mechanisms through which SCNA results in PD have been postulated to be crucial to the pathogenesis of PD. These include distortion in transcription and splicing mechanisms of the α-synuclein gene. In addition, posttranscriptional processes that lead to instability in the mRNA have been suggested as one of the mechanisms leading to SNCA-associated PD. There has been contradicting evidence as per which mechanisms are involved in SCNA associated PD but evidence from Genome-wide association studies (GWAS) show that all these mechanisms may play a role either singly or in conjunction with each other in the pathogenesis of both familial and sporadic forms of PD.
Crucial steps in dopamine homeostasis are under the influence of α-Synuclein
In PD, the bulk of the neurons affected are those of the SNc leading to a myriad of motor symptoms. Understanding the precise mechanisms of dopamine homeostasis remains a chief problem in PD. Production of dopamine has been shown to be influenced by α-synuclein as the protein is believed to decrease the activity of tyrosine hydroxylase (TH), the rate-limiting enzyme in the production of dopamine.
Furthermore, other studies carried out in mice show that α-Synuclein may be involved in decreased release of dopamine from depletion of dopaminergic vesicles at the presynaptic nerve terminal. In addition, α-Synuclein impairs the recycling of the neurotransmitter especially in the hippocampus region of the brain. These mechanisms may underlie the effects of α-Synuclein in the pathogenesis of PD. Research has shown that α-Synuclein affects the dopamine transporter impairing its uptake.
Distinctive characteristics account for selective neurodegeneration of dopaminergic neurons
Dopaminergic neurons are distinct from other neurons that occur in the brain. Studies have shown that in PD patients, SNc neurons have exceptionally elevated rates of high levels of mitochondrial DNA deletions that result in the death of these neurons and as such, may precipitate neurodegenration. Furthermore, products of dopamine metabolism (dopamine adducts) are highly toxic and may be involved in free radical-mediated destruction of the neurons.
Multifaceted effects of α-Synuclein dysfunction on dopaminergic neurons
It has been postulated that, the dysfunction of α-Synuclein may result in numerous deleterious effects that in turn interact to bring about neurodegenration and subsequent PD. These effects include elevation of calcium levels, synaptic vessel damage, and auto-oxidation, all of which may in one way or another bring about neurodegeneration.
Conclusion
It is evident that α-Synuclein plays a role in the pathogenesis of both familial and sporadic forms of PD. In this regard, further research needs to be carried out to map out the molecular basis of the effects of α-Synuclein on SNc. In addition, the distinctive properties that lead to natural degeneration of dopaminergic neurons should be identified in order to fully understand the pathogenesis of PD and to allow for formulation of specific treatment modalities.
References
Venda, L.L., Cragg, S.J., Buchman, V.L., & Wade-Martins, R. (2010). α-Synuclein and dopamine at the crossroads of Parkinson’s disease. Trends in Neurosciences, 33(12), 559-569.