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

Abstract

Introduction: 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.

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

Expert opinion: 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.

Keywords::

• Aggregation
• amyloid
• exosomes
• inclusion
• Lewy body
• Lewy body dementia
• multiple system atrophy
• oligomerization
• Parkinson's disease
• propagation
• release
• substantia nigra
• transgenic models
• viral transduction

Notes

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