Models of α-synuclein aggregation in Parkinson's disease

Acta Neuropathol Commun. 2014 Dec 13;2:176. doi: 10.1186/s40478-014-0176-9.

Abstract

Parkinson's disease (PD) is not only characterized by motor disturbances but also, by cognitive, sensory, psychiatric and autonomic dysfunction. It has been proposed that some of these symptoms might be related to the widespread pathology of α-synuclein (α-syn) aggregation in different nuclei of the central and peripheral nervous system. However, the pathogenic formation of α-syn aggregates in different brain areas of PD patients is poorly understood. Most experimental models of PD are valuable to assess specific aspects of its pathogenesis, such as toxin-induced dopaminergic neurodegeneration. However, new models are required that reflect the widespread and progressive formation of α-syn aggregates in different brain areas. Such α-syn aggregation is induced in only a few animal models, for example perikaryon inclusions are found in rats administered rotenone, aggregates with a neuritic morphology develop in mice overexpressing either mutated or wild-type α-syn, and in Smad3 deficient mice, aggregates form extensively in the perikaryon and neurites of specific brain nuclei. In this review we focus on α-syn aggregation in the human disorder, its genetics and the availability of experimental models. Indeed, evidences show that dopamine (DA) metabolism may be related to α-syn and its conformational plasticity, suggesting an interesting link between the two pathological hallmarks of PD: dopaminergic neurodegeneration and Lewy body (LB) formation.

Publication types

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

MeSH terms

  • Animals
  • Disease Models, Animal*
  • Dopamine / metabolism
  • Glucosylceramidase / genetics
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Lewy Bodies / metabolism
  • Mice
  • Mutation
  • Parkinson Disease / genetics
  • Parkinson Disease / metabolism*
  • Parkinson Disease / pathology
  • Protein Aggregates
  • Protein-Serine-Threonine Kinases / genetics
  • Rats
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism*
  • alpha-Synuclein / toxicity

Substances

  • Protein Aggregates
  • alpha-Synuclein
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Protein-Serine-Threonine Kinases
  • Glucosylceramidase
  • Dopamine