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

Introduction: alpha-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 alpha-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 alpha-Synuclein species are the offending toxic agents. The total amount of alpha-Synuclein is a significant factor that determines its toxicity. alpha-Synuclein can also be secreted and can thus affect neuronal and glial function. Propagation of alpha-Synuclein pathology via neuron-to-neuron transmission and seeding may also contribute to Parkinson's disease pathogenesis. Areas covered: Key mechanisms of deregulation of alpha-Synuclein that could be relevant to neurodegeneration, and could offer opportunities for therapeutic intervention. Expert opinion: Counteracting intracellular and extracellular effects of alpha-Synuclein represents a valid therapeutic target in neurodegeneration. In particular, strategies that target alpha-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.