The role of alpha-synuclein in neurodegenerative diseases

Pharmacol Ther. 2005 Mar;105(3):311-31. doi: 10.1016/j.pharmthera.2004.10.010. Epub 2004 Dec 8.


Alpha-synuclein is a 140 amino acid neuronal protein that has been associated with several neurodegenerative diseases. A point mutation in the gene coding for the alpha-synuclein protein was the first discovery linking this protein to a rare familial form of Parkinson's disease (PD). Subsequently, other mutations in the alpha-synuclein gene have been identified in familial PD. The aggregated proteinaceous inclusions called Lewy bodies found in PD and cortical Lewy body dementia (LBD) were discovered to be predominantly alpha-synuclein. Aberrant aggregation of alpha-synuclein has been detected in an increasing number of neurodegenerative diseases, collectively known as synucleopathies. Alpha-synuclein exists physiologically in both soluble and membrane-bound states, in unstructured and alpha-helical conformations, respectively. The physiological function of alpha-synuclein appears to require its translocation between these subcellular compartments and interconversion between the 2 conformations. Abnormal processing of alpha-synuclein is predicted to lead to pathological changes in its binding properties and function. In this review, genetic and environmental risk factors for alpha-synuclein pathology are described. Various mechanisms for in vitro and in vivo alpha-synuclein aggregation and neurotoxicity are summarized, and their relevance to neuropathology is explored.

Publication types

  • Review

MeSH terms

  • Animals
  • Brain / metabolism*
  • Brain / physiology
  • Humans
  • Nerve Tissue Proteins* / isolation & purification
  • Nerve Tissue Proteins* / physiology
  • Nerve Tissue Proteins* / toxicity
  • Neurodegenerative Diseases* / etiology
  • Neurodegenerative Diseases* / metabolism
  • Rats
  • Synucleins
  • alpha-Synuclein


  • Nerve Tissue Proteins
  • SNCA protein, human
  • Snca protein, rat
  • Synucleins
  • alpha-Synuclein