@article{0d62458c69b04a159258136c6258c672,
title = "The human brainome: Network analysis identifies HSPA2 as a novel Alzheimer's disease target",
abstract = "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-b40 and amyloid-b42 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.",
keywords = "Alzheimer's disease, dementia, genetic network, proteomics, transcriptomics",
author = "Petyuk, {Vladislav A.} and Rui Chang and Manuel Ramirez-Restrepo and Beckmann, {Noam D.} and Henrion, {Marc Y.R.} and Piehowski, {Paul D.} and Kuixi Zhu and Sven Wang and Jennifer Clarke and Huentelman, {Matthew J.} and Fang Xie and Victor Andreev and Anzhelika Engel and Toumy Guettoche and Loida Navarro and {De Jager}, Philip and Schneider, {Julie A.} and Morris, {Christopher M.} and McKeith, {Ian G.} and Perry, {Robert H.} and Simon Lovestone and Woltjer, {Randall L.} and Beach, {Thomas G.} and Sue, {Lucia I.} and Serrano, {Geidy E.} and Lieberman, {Andrew P.} and Albin, {Roger L.} and Isidre Ferrer and Mash, {Deborah C.} and Hulette, {Christine M.} and Ervin, {John F.} and Reiman, {Eric M.} and Hardy, {John A.} and Bennett, {David A.} and Eric Schadt and Smith, {Richard D.} and Myers, {Amanda J.}",
note = "Funding Information: We thank the patients and their families for their selfless donations. Many data and biomaterials were collected from several National Institute on Aging (NIA) and National Alzheimer{\textquoteright}s Coordinating Center (NACC, grant #U01 AG016976) funded sites. Amanda J. Myers, PhD (University of Miami, Department of Psychiatry) and John A. Hardy, PhD (Reta Lila Weston Institute, University College London) collected and prepared the series. Marcelle Morrison-Bogorad, PhD., Tony Phelps, PhD and Walter Kukull PhD are thanked for helping to co-ordinate this collection. The directors, pathologist and technicians involved include: National Institute on Aging: Ruth Seemann, John Hopkins Alzheimer{\textquoteright}s Disease Research Center (NIA grant # AG05146): Juan C. Troncoso, MD, Dr. Olga Pletnikova, University of California, Los Angeles (NIA grant # P50 AG16570):Harry Vinters, MD, Justine Pomakian, The Kathleen Price Bryan Brain Bank, Duke University Medical Center (NIA grant #AG05128, NINDS grant # NS39764, NIMH MH60451 also funded by Glaxo Smith Kline): Christine Hulette, MD, Director, John F. Ervin, Stanford University: Dikran Horoupian, MD, Ahmad Salehi, MD, PhD, Massachusetts Alzheimer{\textquoteright}s Disease Research Center (P50 AG005134): E. Tessa Hedley-Whyte, MD, MP Frosch, MD, Karlotta Fitch, University of Michigan (NIH grant P50-AG053760): Dr. Roger Albin, Lisa Bain, Eszter Gombosi, University of Kentucky (NIH #AG05144): William Markesbery, MD, Sonya Anderson, Mayo Clinic, Jacksonville: Dennis W. Dickson, MD, Natalie Thomas, Washington University, St Louis Alzheimer{\textquoteright}s Disease Research Center (NIH #P50AG05681): Dan McKeel, MD, John C. Morris, MD, Eugene Johnson, Jr., PhD, Virginia Buckles, PhD, Deborah Carter, University of Washington, Seattle (NIH #P50 AG05136):Thomas Montine, MD, PhD, Aimee Schantz, MEd., Boston University Alzheimer{\textquoteright}s Disease Research Center (NIH grant P30-AG13846): Ann C. McKee, Carol Kubilus Banner Sun Health Research Institute Brain Donation Program of Sun City, Arizona (NIA #P30 AG19610; Arizona Alzheimer{\textquoteright}s Disease Core Center, Arizona Department of Health Services, contract 211002, Arizona Alzheimer{\textquoteright}s Research Center; Arizona Biomedical Research Commission, contracts 4001, 0011, 05_901 and 1001 to the Arizona Parkinson{\textquoteright}s Disease Consortium; Michael J. Fox Foundation for Parkinson{\textquoteright}s Research): Thomas G. Beach, MD, PhD, Lucia I. Sue, Geidy E. Serrano; Emory University: Bruce H. Wainer, MD, PhD, Marla Gearing, PhD, University of Texas, Southwestern Medical School: Charles L. White, III, M.D., Roger Rosenberg, Marilyn Howell, Joan Reisch, Rush University Medical Center, Rush Alzheimer{\textquoteright}s Disease Center (NIH #AG10161): David A. Bennett, M.D. Julie A. Schneider, MD, MS, Karen Skish, MS, PA (ASCP)MT, Wayne T Longman, University of Miami Brain Endowment Bank (supported in part by HHSN-271-2013-00030C and the McGowan Endowment): Deborah C. Mash, MD, Margaret J Basile, Mitsuko Tanaka, Oregon Health and Science University: Randy Wotljer, PhD. Funding Information: This project was supported by grants from the National Center for Research Resources (P41RR018522) and the National Institute of General Medical Sciences (P41GM103493) from the National Institutes of Health as well as NIH EUREKA grant AG034504 to A.J.M. and NIA AG041232 to A.J.M and M.H. Tissue resources from the University of Michigan were funded by NIH grant P50-AG08671. Portions of this work were supported by NIH P41GM103493 (to R.D.S).The proteomics work was performed in the Environmental Molecular Science Laboratory, a U.S. Department of Energy (DOE) national scientific user facility at Pacific Northwest National Laboratory (PNNL) in Richland, WA. Battelle operates PNNL for the DOE under contract DE-AC05-76RLO 1830. Publisher Copyright: {\textcopyright} The Author(s) (2018).",
year = "2018",
month = sep,
day = "1",
doi = "10.1093/brain/awy215",
language = "English",
volume = "141",
pages = "2721--2739",
journal = "Brain",
issn = "0006-8950",
publisher = "Oxford University Press",
number = "9",
}