Swedish Alzheimer mutation induces mitochondrial dysfunction mediated by HSP60 mislocalization of amyloid precursor protein (APP) and beta-amyloid
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Swedish Alzheimer mutation induces mitochondrial dysfunction mediated by HSP60 mislocalization of amyloid precursor protein (APP) and beta-amyloid. / Walls, Ken Carlson; Coskun, Pinar; Gallegos-Perez, Jose Luis; Zadourian, Nineli; Freude, Karla Kristine; Rasool, Suhail; Blurton-Jones, Mathew; Green, Kim Nicholas; LaFerla, Frank Michael.
In: Journal of Biological Chemistry, Vol. 287, No. 36, 2012, p. 30317-30327.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Swedish Alzheimer mutation induces mitochondrial dysfunction mediated by HSP60 mislocalization of amyloid precursor protein (APP) and beta-amyloid
AU - Walls, Ken Carlson
AU - Coskun, Pinar
AU - Gallegos-Perez, Jose Luis
AU - Zadourian, Nineli
AU - Freude, Karla Kristine
AU - Rasool, Suhail
AU - Blurton-Jones, Mathew
AU - Green, Kim Nicholas
AU - LaFerla, Frank Michael
PY - 2012
Y1 - 2012
N2 - Alzheimer disease (AD) is a complex disorder that involves numerous cellular and subcellular alterations including impairments in mitochondrial homeostasis. To better understand the role of mitochondrial dysfunction in the pathogenesis of AD, we analyzed brains from clinically well-characterized human subjects and from the 3xTg-AD mouse model of AD. We find Aβ and critical components of the γ-secretase complex, presenilin-1, -2, and nicastrin, accumulate in the mitochondria. We used a proteomics approach to identify binding partners and show that heat shock protein 60 (HSP60), a molecular chaperone localized to mitochondria and the plasma membrane, specifically associates with APP. We next generated stable neural cell lines expressing human wild-type or Swedish APP, and provide corroborating in vitro evidence that HSP60 mediates translocation of APP to the mitochondria. Viral-mediated shRNA knockdown of HSP60 attenuates APP and Aβ mislocalization to the mitochondria. Our findings identify a novel interaction between APP and HSP60, which accounts for its translocation to the mitochondria.
AB - Alzheimer disease (AD) is a complex disorder that involves numerous cellular and subcellular alterations including impairments in mitochondrial homeostasis. To better understand the role of mitochondrial dysfunction in the pathogenesis of AD, we analyzed brains from clinically well-characterized human subjects and from the 3xTg-AD mouse model of AD. We find Aβ and critical components of the γ-secretase complex, presenilin-1, -2, and nicastrin, accumulate in the mitochondria. We used a proteomics approach to identify binding partners and show that heat shock protein 60 (HSP60), a molecular chaperone localized to mitochondria and the plasma membrane, specifically associates with APP. We next generated stable neural cell lines expressing human wild-type or Swedish APP, and provide corroborating in vitro evidence that HSP60 mediates translocation of APP to the mitochondria. Viral-mediated shRNA knockdown of HSP60 attenuates APP and Aβ mislocalization to the mitochondria. Our findings identify a novel interaction between APP and HSP60, which accounts for its translocation to the mitochondria.
KW - Alzheimer Disease
KW - Amyloid
KW - Amyloid Precursor Protein Secretases
KW - Amyloid beta-Protein Precursor
KW - Animals
KW - Brain
KW - Cell Line
KW - Chaperonin 60
KW - Disease Models, Animal
KW - Humans
KW - Mice
KW - Mice, Transgenic
KW - Mitochondria
KW - Mitochondrial Proteins
KW - Protein Transport
U2 - 10.1074/jbc.M112.365890
DO - 10.1074/jbc.M112.365890
M3 - Journal article
C2 - 22753410
VL - 287
SP - 30317
EP - 30327
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 36
ER -
ID: 138433687