Targeting α-synuclein for treatment of Parkinson's disease: mechanistic and therapeutic considerations

Lancet Neurol. 2015 Aug;14(8):855-866. doi: 10.1016/S1474-4422(15)00006-X. Epub 2015 Jun 3.


Progressive neuronal cell loss in a small subset of brainstem and mesencephalic nuclei and widespread aggregation of the α-synuclein protein in the form of Lewy bodies and Lewy neurites are neuropathological hallmarks of Parkinson's disease. Most cases occur sporadically, but mutations in several genes, including SNCA, which encodes α-synuclein, are associated with disease development. The discovery and development of therapeutic strategies to block cell death in Parkinson's disease has been limited by a lack of understanding of the mechanisms driving neurodegeneration. However, increasing evidence of multiple pivotal roles of α-synuclein in the pathogenesis of Parkinson's disease has led researchers to consider the therapeutic potential of several strategies aimed at reduction of α-synuclein toxicity. We critically assess the potential of experimental therapies targeting α-synuclein, and discuss steps that need to be taken for target validation and drug development.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Drug Discovery*
  • Humans
  • Parkinson Disease / drug therapy*
  • Parkinson Disease / metabolism*
  • alpha-Synuclein / chemistry
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism*


  • alpha-Synuclein