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Roy N. Alcalay, M.D.
"Why do some people who carry genetic mutations associated with Parkinson’s disease (PD) never develop PD while others do?" asks Roy N. Alcalay, M.D., a postdoctoral fellow at the Center for Parkinson’s Disease and Other Movement Disorders...
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Parkin reverses intracellular beta-amyloid accumulation and its negative effects on proteasome function.
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J Neurosci Res 2009 Jul;
Authors: Kenneth M Rosen, Charbel E-H Moussa, Han-Kyu Lee, Pravir Kumar, Tohru Kitada, Gangjian Qin, Qinghao Fu, Henry W Querfurth
Department of Neurology, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts.
The significance of intracellular beta-amyloid (Abeta(42)) accumulation is increasingly recognized in Alzheimer's disease (AD) pathogenesis. Abeta 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 Abeta 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 Abeta(42), an action abrogated by proteasome inhibitors. Intracellular Abeta(42) accumulation decreased cell viability and proteasome activity. Accordingly, Parkin reversed both effects. Changes in mitochondrial ATP production from Abeta or Parkin did not account for their effects on the proteasome. Parkin knock-down led to accumulation of Abeta. In AD brain, Parkin was found to interact with Abeta and its levels were reduced. Thus, Parkin is cytoprotective, partially by increasing the removal of cellular Abeta through a proteasome-dependent pathway. (c) 2009 Wiley-Liss, Inc.
PMID: 19610108 [PubMed - as supplied by publisher]
