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Expert Opin Ther Targets. 2012 Apr;16(4):421-32. doi: 10.1517/14728222.2012.674111.

Targeting intracellular and extracellular alpha-synuclein as a therapeutic strategy in Parkinson's disease and other synucleinopathies.

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Center for Neurosciences, Biomedical Research Foundation of the Academy of Athens, Greece.



α-Synuclein is a neuronal presynaptic protein that regulates neurotransmitter release. Genetic, neuropathological, biochemical and animal model data indicate that it plays a major role in Parkinson's disease and other neurodegenerative disorders, acting through a toxic gain of function. Although the mechanism of the toxic function of α-Synuclein is not yet certain, it may involve multiple intracellular targets of the aberrantly misfolded, aggregated protein. It is generally thought that specific soluble oligomeric α-Synuclein species are the offending toxic agents. The total amount of α-Synuclein is a significant factor that determines its toxicity. α-Synuclein can also be secreted and can thus affect neuronal and glial function. Propagation of α-Synuclein pathology via neuron-to-neuron transmission and seeding may also contribute to Parkinson's disease pathogenesis.


Key mechanisms of deregulation of α-Synuclein that could be relevant to neurodegeneration, and could offer opportunities for therapeutic intervention.


Counteracting intracellular and extracellular effects of α-Synuclein represents a valid therapeutic target in neurodegeneration. In particular, strategies that target α-Synuclein through limitation of its burden at the transcriptional and post-transcriptional level, inhibition of its aggregation or of aberrant phosphorylation states, immunization or attenuation of its secretion and propagation may be therapeutic options.

[Indexed for MEDLINE]

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