Synphilin isoforms and the search for a cellular model of lewy body formation in Parkinson's disease

Cell Cycle. 2006 Sep;5(18):2082-6. doi: 10.4161/cc.5.18.3209. Epub 2006 Sep 15.

Abstract

A common finding in many neurodegenerative diseases is the presence of inclusion bodies made of aggregated proteins in neurons of affected brain regions. In Parkinson's disease, the inclusion bodies are referred to as Lewy bodies and their main component is alpha-synuclein. Although many studies have suggested that inclusion bodies may be cell protective, it is still not clear whether Lewy bodies promote or inhibit dopaminergic cell death in Parkinson's disease. Synphilin-1 interacts with alpha-synuclein and is present in Lewy bodies. Accumulation of ubiquitylated synphilin-1 leads to massive formation of inclusion bodies, which resemble Lewy bodies by their ability to recruit alpha-synuclein. We have recently isolated an isoform of synphilin-1, synphilin-1A, that spontaneously aggregates in cells, and is present in detergent-insoluble fractions of brain protein samples from alpha-synucleinopathy patients. Synphilin-1A displays marked neuronal toxicity and, upon proteasome inhibition, accumulates into ubiquitylated inclusions with concomitant reduction of its intrinsic toxicity. The fact that alpha-synuclein interacts with synphilin-1A, and is recruited to synphilin-1A inclusion bodies in neurons together with synphilin-1, further indicates that synphilin-1A cell model is relevant for research on Parkinson's disease. Synphilin-1A cell model may help provide important insights regarding the role of inclusion bodies in Parkinson's disease and other neurodegenerative disorders.

Publication types

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

MeSH terms

  • Animals
  • Brain / metabolism*
  • Brain / pathology
  • Brain / physiopathology
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Genetic Predisposition to Disease / genetics
  • Humans
  • Lewy Bodies / genetics
  • Lewy Bodies / metabolism*
  • Lewy Bodies / pathology
  • Models, Biological
  • Mutation / genetics
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Parkinson Disease / genetics
  • Parkinson Disease / metabolism*
  • Parkinson Disease / physiopathology
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Ubiquitin / metabolism
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism

Substances

  • Carrier Proteins
  • Nerve Tissue Proteins
  • Protein Isoforms
  • SNCAIP protein, human
  • Ubiquitin
  • alpha-Synuclein