Parkin reverses intracellular β-amyloid accumulation and its negative effects on proteasome function

Kenneth M. Rosen, Charbel E H Moussa, Han Kyu Lee, Pravir Kumar, Tohru Kitada, Gangjian Qin, Qinghao Fu, Henry W. Querfurth

Research output: Contribution to journalArticle

58 Scopus citations

Abstract

The significance of intracellular β-amyloid (Aβ42) accumulation is increasingly recognized in Alzheimer's disease (AD) pathogenesis. Aβ removal mechanisms that have attracted attention include IDE/neprilysin degradation and antibody-mediated uptake by immune cells. However, the role of the ubiquitin-proteasome system (UPS) in the disposal of cellular Aβ has not been fully explored. The E3 ubiquitin ligase Parkin targets several proteins for UPS degradation, and Parkin mutations are the major cause of autosomal recessive Parkinson's disease. We tested whether Parkin has cross-function to target misfolded proteins in AD for proteasome-dependent clearance in SH-SY5Y and primary neuronal cells. Wild-type Parkin greatly decreased steady-state levels of intracellular Aβ42, an action abrogated by proteasome inhibitors. Intracellular Aβ42 accumulation decreased cell viability and proteasome activity. Accordingly, Parkin reversed both effects. Changes in mitochondrial ATP production from Aβ or Parkin did not account for their effects on the proteasome. Parkin knock-down led to accumulation of Aβ. In AD brain, Parkin was found to interact with Aβ and its levels were reduced. Thus, Parkin is cytoprotective, partially by increasing the removal of cellular Aβ through a proteasome-dependent pathway.

Original languageEnglish (US)
Pages (from-to)167-178
Number of pages12
JournalJournal of Neuroscience Research
Volume88
Issue number1
DOIs
StatePublished - Jan 2010

Keywords

  • Alzheimer's
  • Amyloid
  • Parkin
  • Proteasome
  • Ubiquitin ligase

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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    Rosen, K. M., Moussa, C. E. H., Lee, H. K., Kumar, P., Kitada, T., Qin, G., Fu, Q., & Querfurth, H. W. (2010). Parkin reverses intracellular β-amyloid accumulation and its negative effects on proteasome function. Journal of Neuroscience Research, 88(1), 167-178. https://doi.org/10.1002/jnr.22178