The human brainome: network analysis identifies HSPA2 as a novel Alzheimer's disease target

Vladislav A Petyuk; Rui Chang; Manuel Ramirez-Restrepo; Noam D Beckmann; Marc Y R Henrion; Paul D Piehowski; Kuixi Zhu; Sven Wang; Jennifer Clarke; Matthew J Huentelman; Fang Xie; Victor Andreev; Anzhelika Engel; Toumy Guettoche; Loida Navarro; Philip De Jager; Julie A Schneider; Christopher M Morris; Ian G McKeith; Robert H Perry; Simon Lovestone; Randall L Woltjer; Thomas G Beach; Lucia I Sue; Geidy E Serrano; Andrew P Lieberman; Roger L Albin; Isidre Ferrer; Deborah C Mash; Christine M Hulette; John F Ervin; Eric M Reiman; John A Hardy; David A Bennett; Eric Schadt; Richard D Smith; Amanda J Myers

doi:10.1093/brain/awy215

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The human brainome: network analysis identifies HSPA2 as a novel Alzheimer's disease target

Journal article

Open access

Peer reviewed

The human brainome: network analysis identifies HSPA2 as a novel Alzheimer's disease target

Vladislav A Petyuk, Rui Chang, Manuel Ramirez-Restrepo, Noam D Beckmann, Marc Y R Henrion, Paul D Piehowski, Kuixi Zhu, Sven Wang, Jennifer Clarke, Matthew J Huentelman, …

Brain (London, England : 1878), Vol.141(9), pp.2721-2739

2018-09-01

DOI: https://doi.org/10.1093/brain/awy215

PMID: 30137212

Abstract

Cell Line

Alzheimer Disease - physiopathology

RNA - analysis

Humans

Gene Expression Profiling - methods

HSP70 Heat-Shock Proteins - genetics

Male

Transcriptome - genetics

Brain Mapping - methods

HSP70 Heat-Shock Proteins - metabolism

Brain - metabolism

Alzheimer Disease - metabolism

HEK293 Cells

Aged, 80 and over

Female

HSP70 Heat-Shock Proteins - physiology

Aged

Protein Processing, Post-Translational

Alzheimer Disease - genetics

Nerve Net - physiopathology

RNA - metabolism

Our hypothesis is that changes in gene and protein expression are crucial to the development of late-onset Alzheimer's disease. Previously we examined how DNA alleles control downstream expression of RNA transcripts and how those relationships are changed in late-onset Alzheimer's disease. We have now examined how proteins are incorporated into networks in two separate series and evaluated our outputs in two different cell lines. Our pipeline included the following steps: (i) predicting expression quantitative trait loci; (ii) determining differential expression; (iii) analysing networks of transcript and peptide relationships; and (iv) validating effects in two separate cell lines. We performed all our analysis in two separate brain series to validate effects. Our two series included 345 samples in the first set (177 controls, 168 cases; age range 65-105; 58% female; KRONOSII cohort) and 409 samples in the replicate set (153 controls, 141 cases, 115 mild cognitive impairment; age range 66-107; 63% female; RUSH cohort). Our top target is heat shock protein family A member 2 (HSPA2), which was identified as a key driver in our two datasets. HSPA2 was validated in two cell lines, with overexpression driving further elevation of amyloid-β40 and amyloid-β42 levels in APP mutant cells, as well as significant elevation of microtubule associated protein tau and phosphorylated-tau in a modified neuroglioma line. This work further demonstrates that studying changes in gene and protein expression is crucial to understanding late onset disease and further nominates HSPA2 as a specific key regulator of late-onset Alzheimer's disease processes.10.1093/brain/awy215_video1awy215media15824729224001.

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.52 Neurodegenerative Diseases; 1.52.57 Alzheimer's Disease
Web Of Science research areas: Clinical Neurology; Neurosciences
ESI research areas: Neuroscience & Behavior

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Title: The human brainome: network analysis identifies HSPA2 as a novel Alzheimer's disease target
Creators: Vladislav A Petyuk - Biological Sciences Division and Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, WA, USA
Rui Chang - Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Manuel Ramirez-Restrepo - Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, USA
Noam D Beckmann - Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Marc Y R Henrion - Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Paul D Piehowski - Biological Sciences Division and Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, WA, USA
Kuixi Zhu - Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Sven Wang - Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Jennifer Clarke - Food Science and Technology Department, University of Nebraska-Lincoln, Lincoln, NE, USA
Matthew J Huentelman - Neurogenomics Division, The Translational Genomics Research Institute, Phoenix, AZ, USA
Fang Xie - Biological Sciences Division and Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, WA, USA
Victor Andreev - Arbor Research Collaborative for Health, 340 E Huron St # 300, Ann Arbor, MI, USA
Anzhelika Engel - Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, USA
Toumy Guettoche - Roche Sequencing, 4300 Hacienda Drive, Pleasanton, CA, USA
Loida Navarro - Roche Sequencing, 4300 Hacienda Drive, Pleasanton, CA, USA
Philip De Jager - Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
Julie A Schneider - Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA
Christopher M Morris - Newcastle Brain Tissue Resource, Institute of Neuroscience, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, UK
Ian G McKeith - NIHR Biomedical Research Centre, Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK
Robert H Perry - Neuropathology and Cellular Pathology, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne, UK
Simon Lovestone - University of Oxford, Medical Sciences Division, Department of Psychiatry, Warneford Hospital, Oxford, UK
Randall L Woltjer - Neuropathology Core of the Layton Aging and Alzheimer's Disease Center, Oregon Health and Science University, Portland, OR, USA
Thomas G Beach - Banner Sun Health Research Institute, Sun City, AZ, USA
Lucia I Sue - Banner Sun Health Research Institute, Sun City, AZ, USA
Geidy E Serrano - Banner Sun Health Research Institute, Sun City, AZ, USA
Andrew P Lieberman - Department of Pathology, University of Michigan, Ann Arbor, MI, USA
Roger L Albin - Geriatrics Research, Education, and Clinical Center, VAAAHS, Ann Arbor, MI, USA
Isidre Ferrer - Department of Pathology and Experimental Therapeutics, University of Barcelona; CIBERNED; Hospitalet de Llobregat, Spain
Deborah C Mash - Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA
Christine M Hulette - Department of Pathology, Division of Neuropathology, Duke University Medical Center, Durham, NC, USA
John F Ervin - Kathleen Price Bryan Brain Bank, Department of Medicine, Division of Neurology, Duke University, Durham, NC, USA
Eric M Reiman - Banner Alzheimer's Institute, Phoenix, Arizona, USA
John A Hardy - Department of Molecular Neuroscience and Reta Lila Research Laboratories, University College London Institute of Neurology, London, UK
David A Bennett - Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA
Eric Schadt - Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Richard D Smith - Biological Sciences Division and Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, WA, USA
Amanda J Myers - Interdepartmental Program in Human Genetics and Genomics, University of Miami Miller School of Medicine, Miami, FL, USA
Publication Details: Brain (London, England : 1878), Vol.141(9), pp.2721-2739
Publisher: England
Grant note: R01 AG041232 / NIA NIH HHS P41 GM103493 / NIGMS NIH HHS P50 NS039764 / NINDS NIH HHS P50 AG005144 / NIA NIH HHS P50 AG005146 / NIA NIH HHS U01 AG016976 / NIA NIH HHS R01 AG017917 / NIA NIH HHS P30 AG019610 / NIA NIH HHS P50 MH060451 / NIMH NIH HHS P30 AG013846 / NIA NIH HHS R01 AG034504 / NIA NIH HHS RF1 AG015819 / NIA NIH HHS P50 AG005136 / NIA NIH HHS G0502157 / Medical Research Council P50 AG016570 / NIA NIH HHS P50 AG005134 / NIA NIH HHS P50 AG005681 / NIA NIH HHS G1100540 / Medical Research Council P30 AG010161 / NIA NIH HHS P50 AG005128 / NIA NIH HHS G0400074 / Medical Research Council G0900652 / Medical Research Council P30 AG053760 / NIA NIH HHS
Academic Unit: Miller School of Medicine; Cell Biology Research; UMMG Department of Neurology
Language: English
Resource Type: Journal article
PMID: 30137212
Record Identifier: 991031577509902976