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

Authors

  • Kenneth M. Rosen,

    1. Department of Neurology, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts
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    • K.M.R. and C.E.-H.M. as well as H.-K.L. and P.K. contributed equally to this work.

  • Charbel E.-H. Moussa,

    1. Department of Neurology, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts
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    • K.M.R. and C.E.-H.M. as well as H.-K.L. and P.K. contributed equally to this work.

  • Han-Kyu Lee,

    1. Department of Neurology, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts
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    • K.M.R. and C.E.-H.M. as well as H.-K.L. and P.K. contributed equally to this work.

  • Pravir Kumar,

    1. Department of Neurology, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts
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    • K.M.R. and C.E.-H.M. as well as H.-K.L. and P.K. contributed equally to this work.

  • Tohru Kitada,

    1. Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, Massachusetts
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  • Gangjian Qin,

    1. Department of Cardiovascular Research, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts
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  • Qinghao Fu,

    1. Department of Neurology, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts
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  • Henry W. Querfurth

    Corresponding author
    1. Department of Neurology, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts
    • Department of Neurology, Caritas St. Elizabeth's Medical Center, 736 Cambridge St., Boston, MA 02111
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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. © 2009 Wiley-Liss, Inc.

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