Swedish Alzheimer mutation induces mitochondrial dysfunction mediated by HSP60 mislocalization of amyloid precursor protein (APP) and beta-amyloid

Ken Carlson Walls; Pinar Coskun; Jose Luis Gallegos-Perez; Nineli Zadourian; Karla Kristine Freude; Suhail Rasool; Mathew Blurton-Jones; Kim Nicholas Green; Frank Michael LaFerla

doi:10.1074/jbc.M112.365890

Swedish Alzheimer mutation induces mitochondrial dysfunction mediated by HSP60 mislocalization of amyloid precursor protein (APP) and beta-amyloid

Ken Carlson Walls, Pinar Coskun, Jose Luis Gallegos-Perez, Nineli Zadourian, Karla Kristine Freude, Suhail Rasool, Mathew Blurton-Jones, Kim Nicholas Green, Frank Michael LaFerla

48 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Journal of Biological Chemistry
Volume	287
Issue number	36
Pages (from-to)	30317-30327
Number of pages	11
ISSN	0021-9258
DOIs	https://doi.org/10.1074/jbc.M112.365890
Publication status	Published - 31 Aug 2012
Externally published	Yes

Keywords

Alzheimer Disease
Amyloid
Amyloid Precursor Protein Secretases
Amyloid beta-Protein Precursor
Animals
Brain
Cell Line
Chaperonin 60
Disease Models, Animal
Humans
Mice
Mice, Transgenic
Mitochondria
Mitochondrial Proteins
Protein Transport

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1074/jbc.M112.365890

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Walls, K. C., Coskun, P., Gallegos-Perez, J. L., Zadourian, N., Freude, K. K., Rasool, S., Blurton-Jones, M., Green, K. N., & LaFerla, F. M. (2012). Swedish Alzheimer mutation induces mitochondrial dysfunction mediated by HSP60 mislocalization of amyloid precursor protein (APP) and beta-amyloid. Journal of Biological Chemistry, 287(36), 30317-30327. https://doi.org/10.1074/jbc.M112.365890

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 et al.

In: Journal of Biological Chemistry, Vol. 287, No. 36, 31.08.2012, p. 30317-30327.

Research output: Contribution to journal › Journal article › Research › peer-review

Walls, KC, Coskun, P, Gallegos-Perez, JL, Zadourian, N, Freude, KK, Rasool, S, Blurton-Jones, M, Green, KN & LaFerla, FM 2012, 'Swedish Alzheimer mutation induces mitochondrial dysfunction mediated by HSP60 mislocalization of amyloid precursor protein (APP) and beta-amyloid', Journal of Biological Chemistry, vol. 287, no. 36, pp. 30317-30327. https://doi.org/10.1074/jbc.M112.365890

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abstract = "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.",

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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 - 2012/8/31

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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.

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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

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EP - 30327

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 36

ER -

Swedish Alzheimer mutation induces mitochondrial dysfunction mediated by HSP60 mislocalization of amyloid precursor protein (APP) and beta-amyloid

Abstract

Keywords

UN SDGs

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