Since the discovery that mutations in α-synuclein can cause familial Parkinson's disease, there has been great interest in its role in the pathogenesis of the disease. Other genes that have been implicated in familial Parkinson's disease might also influence the structure or clearance of α-synuclein. In Parkinson's disease and other disorders, α-synuclein is found in intraneuronal inclusions called Lewy bodies, and it is proposed that α-synuclein forms oligomers and fibrils before aggregating into Lewy bodies. However, it is unclear whether α-synuclein oligomers, fibrils or Lewy bodies are protective or toxic to neurons.
Interactions between certain α-synuclein conformations and dopamine metabolism might cause selective degeneration of dopamine neurons, as is observed in Parkinson's disease. Dopamine metabolism generates reactive oxygen species, which might accelerate aggregation of α-synuclein, which itself might increase the generation of toxic reactive oxygen species.
Both 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and rotenone are used to generate animal models of Parkinson's disease. MPTP is converted to MPP+, which causes neurodegeneration by entering dopamine neurons through the dopamine transporter and inhibiting mitochondrial complex I. Mice lacking α-synuclein are resistant to the effects of MPTP, and it has been proposed that the increase in reactive oxygen species caused by MPP+ leads to an increase in α-synuclein aggregation which further increases the generation of reactive oxygen species. MPTP does not, however, cause Lewy body formation.
Rotenone is also an inhibitor of mitochondrial complex I, although it enters the cell through a different route to MPP+, and α-synuclein knockout mice are not resistant to its effects. Rats treated with rotenone show nigrostriatal degeneration accompanied by a variety of motor symptoms, and develop Lewy body-like inclusions.
Overexpression of normal or mutant human α-synuclein in non-rodent species can generate genetic models of Parkinson's disease. In flies, which contain no endogenous α-synuclein, α-synuclein expression causes age-related depletion of dopamine neurons. This is proposed to be related to the abnormal aggregation of α-synuclein, and can be prevented by concomitant expression of a molecular chaperone.
Various promoters and α-synuclein transgenes have been used to generate α-synuclein transgenic mice, with variable results. None of the transgenic mice show a true parkinsonian condition that includes Lewy bodies, but some do exhibit loss of dopamine neurons and motor impairments. It is possible that higher and more consistent levels of transgene expression will be needed to create a more useful transgenic mouse model.
Viral vectors have been used to introduce α-synuclein into the brains of rats and monkeys. Again, the results have been variable but this system might also prove useful if expression can be optimized.
No existing animal model shows the full spectrum of features of Parkinson's disease, although the models that do exist complement each other. Continued development of these models should allow studies that elucidate further the pathogenesis of Parkinson's disease, and improve our understanding of the role of α-synuclein in both health and disease.
The abnormal accumulations of fibrillar α-synuclein in Lewy bodies and the mutations in the gene for α-synuclein in familial forms of Parkinson's disease have led to the belief that this protein has a central role in a group of neurodegenerative diseases known as the synucleinopathies. Our understanding of the biology of α-synuclein has increased significantly since its discovery in 1997, and recently developed animal models of the synucleinopathies have contributed to this understanding. The information gleaned from animal models has the potential to provide a framework for continuing the development of rational therapeutic strategies.
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- MISSENSE MUTATION
A mutation that results in the substitution of an amino acid in a protein.
The probability that an individual with a particular genotype manifests a given phenotype. Complete penetrance corresponds to the situation in which every individual with the same specific genotype manifests the phenotype in question.
- ROTAROD TEST
Motor test that probes the ability of rodents to keep their balance on a cylinder that rotates continuously at a slow speed, commonly 5–6 revolutions per minute.
- ADENO-ASSOCIATED VIRUSES
A group of viruses that require co-infection with an adenovirus or a herpesvirus for their replication. If no helper virus is present, the genome of adeno-associated viruses can be integrated into the host DNA, resulting in latent infection.
A group of retroviruses that includes HIV. Virus derivatives that are engineered to be replication-defective can be used as expression vectors. Lentiviral vectors have advantages over retroviral vectors because of their ability to infect non-dividing human cells, particularly neurons.
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Maries, E., Dass, B., Collier, T. et al. The role of α-synuclein in Parkinson's disease: insights from animal models. Nat Rev Neurosci 4, 727–738 (2003). https://doi.org/10.1038/nrn1199
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