Parkin protects against mitochondrial toxins and β-amyloid accumulation in skeletal muscle cells

Academic Article

Abstract

  • Mutations in the ubiquitin ligase-encoding Parkin gene have been implicated in the pathogenesis of autosomal recessive Parkinson disease. Outside of the central nervous system, Parkin is prominently expressed in skeletal muscle. We have found accumulations of Parkin protein in skeletal muscle biopsies taken from patients with inclusion body myositis, a degenerative disorder in which intramyofiber accumulations of the β-amyloid peptide are pathognomonic. In comparing primary cultures of skeletal muscle derived from parkin knock-out and wild-type mice, we have found the absence of parkin to result in greater sensitivity to mitochondrial stressors rotenone and carbonyl cyanide 3-chlorophenylhydrazone, without any alteration in sensitivity to calcium ionophore or hydrogen peroxide. Utilizing viral expression constructs coding for the Alzheimer disease and inclusion body myositis-linked β-amyloid precursor protein and for its metabolic byproducts Aβ42 and C100, we found that parkin knock-out muscle cells are also more sensitive to the toxic effects of intracellular Aβ. We also constructed a lentiviral system to overexpress wild-type Parkin and have shown that boosting the levels of parkin expression in normal skeletal muscle cultures provides substantial protection against both mitochondrial toxins and overexpressed β-amyloid. Correspondingly, exogenous Parkin significantly lowered Aβ levels. These data support the hypothesis that in myocytes parkin has dual properties in the maintenance of skeletal muscle mitochondrial homeostasis and in the regulation of Aβlevels. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.
  • Published In

    Digital Object Identifier (doi)

    Author List

  • Rosen KM; Veereshwarayya V; Moussa CEH; Fu Q; Goldberg MS; Schlossmacher MG; Shen J; Querfurth HW
  • Start Page

  • 12809
  • End Page

  • 12816
  • Volume

  • 281
  • Issue

  • 18