title: Targeting intracellular and extracellular alpha-synuclein as a therapeutic strategy in Parkinson's disease and other synucleinopathies.
abstract: BACKGROUND
  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.
  
  
  METHODS
  Key mechanisms of deregulation of α-Synuclein that could be relevant to neurodegeneration, and could offer opportunities for therapeutic intervention.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Center for Neurosciences, Biomedical Research Foundation of the Academy of Athens, Greece.
authors.forename: Kostas
authors.initials: K
authors.lastname: Vekrellis
authors.forename: Leonidas
authors.initials: L
authors.lastname: Stefanis
mesh_terms: D000818:Animals; D006801:Humans; D007114:Immunization; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism* / Q000628:therapy; D010766:Phosphorylation; D037761:Sirtuins / Q000378:metabolism; D051844:alpha-Synuclein / Q000276:immunology / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein; D037761:Sirtuins