Development of new treatments for Parkinson's disease in transgenic animal models: a role for beta-synuclein

Neurotoxicology. 2002 Oct;23(4-5):461-8. doi: 10.1016/s0161-813x(02)00029-3.

Abstract

Neuronal death in Parkinson's disease (PD), one of the most common neurodegenerative disorders in the adult and aging population is probably caused by misfolding of synaptic proteins such as alpha-synuclein. Although, some treatments are currently available to control some of the symptoms of PD, none of these approaches directly addresses the mechanisms of disease. With the advent of new experimental animal models for this disorder, the potential for development and discovery of new treatment has been significantly bolstered. Among them, overexpression of alpha-synuclein results in motor deficits. dopaminergic loss and formation of inclusion bodies. Co-expression of mutant amyloid precursor protein, accelerates alpha-synuclein aggregation and enhances the neurodegenerative pathology in these mice, providing a unique model where to investigate the interactions between Abeta1-42 and alpha-synuclein and to develop treatments for combined Alzheimer's disease and PD. Development of anti-parkinsonian treatments based on these models includes: (i) anti-aggregation or pro-degradation compounds, (ii) neuroprotective compounds, and (iii) neurotrophic agents. Among them, we characterized beta-synuclein, the non-amyloidogenic homologue of alpha-synuclein, as an inhibitor of aggregation of alpha-synuclein. Our results raise the intriguing possibility that beta-synuclein might be a natural negative regulator of alpha-synuclein aggregation, and that a similar class of endogenous factors might regulate the aggregation state of other molecules involved in neurodegeneration. Such an anti-amyloidogenic property of beta-synuclein might also provide a novel strategy for the treatment of neurodegenerative disorders.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Amyloidosis / drug therapy*
  • Amyloidosis / genetics
  • Amyloidosis / metabolism
  • Animals
  • Animals, Genetically Modified
  • Cell Aggregation
  • Disease Models, Animal
  • Humans
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / physiology*
  • Parkinson Disease, Secondary / drug therapy*
  • Parkinson Disease, Secondary / genetics
  • Parkinson Disease, Secondary / metabolism
  • Protein Binding
  • Protein Folding
  • Synucleins
  • alpha-Synuclein
  • beta-Synuclein

Substances

  • Nerve Tissue Proteins
  • SNCA protein, human
  • SNCB protein, human
  • Synucleins
  • alpha-Synuclein
  • beta-Synuclein