Inclusion body formation and neurodegeneration are parkin independent in a mouse model of α-synucleinopathy

Rainer Von Coelln, Bobby Thomas, Shaida A. Andrabi, Leong Lim Kah, Joseph M. Savitt, Roya Saffary, Wanda Stirling, Kristy Bruno, Ellen J. Hess, Michael K. Lee, Valina L. Dawson, Ted M. Dawson

Research output: Contribution to journalArticle

72 Scopus citations

Abstract

Mutations in the genes coding for α-synuclein and parkin cause autosomal-dominant and autosomal-recessive forms of Parkinson's disease (PD), respectively. α-Synuclein is a major component of Lewy bodies, the proteinaceous cytoplasmic inclusions that are the pathological hallmark of idiopathic PD. Lewy bodies appear to be absent in cases of familial PD associated with mutated forms of parkin. Parkin is an ubiquitin E3 ligase, and it may be involved in the processing and/or degradation of α-synuclein, as well as in the formation of Lewy bodies. Here we report the behavioral, biochemical, and histochemical characterization of double-mutant mice overexpressing mutant human A53T α-synuclein on a parkin null background. We find that the absence of parkin does not have an impact on the onset and progression of the lethal phenotype induced by overexpression of human A53T α-synuclein. Furthermore, all major behavioral, biochemical, and morphological characteristics of A53T α-synuclein-overexpressing mice are not altered in parkin null α-synuclein-overexpressing double-mutant mice. Our results demonstrate that mutant α-synuclein induces neurodegeneration independent of parkin-mediated ubiquitin E3 ligase activity in nondopaminergic systems and suggest that PD caused by α-synuclein and parkin mutations may occur via independent mechanisms.

Original languageEnglish (US)
Pages (from-to)3685-3696
Number of pages12
JournalJournal of Neuroscience
Volume26
Issue number14
DOIs
StatePublished - Apr 5 2006

Keywords

  • Animal models
  • Lewy bodies
  • Neurodegeneration
  • Parkin
  • Parkinson's disease
  • α-synuclein

ASJC Scopus subject areas

  • Neuroscience(all)

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    Von Coelln, R., Thomas, B., Andrabi, S. A., Kah, L. L., Savitt, J. M., Saffary, R., Stirling, W., Bruno, K., Hess, E. J., Lee, M. K., Dawson, V. L., & Dawson, T. M. (2006). Inclusion body formation and neurodegeneration are parkin independent in a mouse model of α-synucleinopathy. Journal of Neuroscience, 26(14), 3685-3696. https://doi.org/10.1523/JNEUROSCI.0414-06.2006