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Parkin reverses intracellular β‐amyloid accumulation and its negative effects on proteasome function
Author(s) -
Rosen Kenneth M.,
Moussa Charbel E.H.,
Lee HanKyu,
Kumar Pravir,
Kitada Tohru,
Qin Gangjian,
Fu Qinghao,
Querfurth Henry W.
Publication year - 2010
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.22178
Subject(s) - parkin , proteasome , ubiquitin ligase , intracellular , ubiquitin , microbiology and biotechnology , protein degradation , biology , chemistry , parkinson's disease , biochemistry , medicine , disease , gene
The significance of intracellular β‐amyloid (Aβ 42 ) 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 Aβ 42 , an action abrogated by proteasome inhibitors. Intracellular Aβ 42 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. © 2009 Wiley‐Liss, Inc.