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Systems Genetics of Neurodegenerative Disease

Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Neurosci. | doi: 10.3389/fnins.2019.00002

A microglial signature directing human aging and neurodegeneration-related gene networks

  • 1Health Informatics Advanced Science Masters program, Arizona State University, United States
  • 2Department of Neurology and Department of Bioinformatics, University of California, Los Angeles, United States
  • 3Institute for Medical Informatics and Biometry, Technische Universität Dresden, Germany
  • 4Neural Regeneration Group, Institute of Reconstructive Neurobiology, Universität Bonn, Germany
  • 5Allen Institute for Brain Science, United States
  • 6Center for Neuropathology and Prion Research, Ludwig Maximilian University of Munich, Germany
  • 7Department of Translational Brain Research, German Center for Neurodegenerative Diseases (DZNE), Germany
  • 8Department of Ophthalmology, Emory University, United States

Aging is regarded as a major risk factor for neurodegenerative diseases. Thus, a better understanding of the similarities between the aging process and neurodegenerative diseases at the cellular and molecular level may reveal better understanding of this detrimental relationship. In the present study, we mined publicly available gene expression datasets from healthy individuals and patients affected by neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease and Huntington's disease) across a broad age spectrum and compared those with mouse aging and mouse cell-type specific gene expression profiles. We performed weighted gene co-expression network analysis (WGCNA) and found a gene network strongly related with both aging and neurodegenerative diseases. This network was significantly enriched with a microglial signature as imputed from cell type-specific sequencing data. Since mouse models are extensively used for the study of human diseases, we further compared these human gene regulatory networks with age-specific mouse brain transcriptomes. We discovered significantly preserved networks with both human aging and human disease and identified 17 shared genes in the top-ranked immune/microglia module, among which we find five human hub genes TYROBP, FCER1G, ITGB2, MYO1F, PTPRC, and 2 mouse hub genes Trem2 and C1qa. Taken together, these results support the hypothesis that microglia are key players involved in human aging and neurodegenerative diseases, and suggest that mouse models should be appropriate for studying these microglial changes in human.

Keywords: Aging, neurodegeneration, Microglia, gene networks, bioinformatics, WGCNA (weighted gene co-expression network analysis), mouse model, Alzheimer, Parkinson, Huntington

Received: 31 Aug 2018; Accepted: 03 Jan 2019.

Edited by:

Rupert W. Overall, German Center for Neurodegenerative Diseases (DZNE), Germany

Reviewed by:

Michael Oldham, University of California, San Francisco, United States
Björn Spittau, Universitätsmedizin Rostock, Germany
Khyobeni Mozhui, University of Tennessee Health Science Center (UTHSC), United States  

Copyright: © 2019 Mukherjee, Pricop-Jeckstadt, Klaus, Miller and Struebing. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Dr. Shradha Mukherjee, Arizona State University, Health Informatics Advanced Science Masters program, Tempe, 85281, Arizona, United States,
Dr. Felix L. Struebing, Ludwig Maximilian University of Munich, Center for Neuropathology and Prion Research, Munich, 80802, Bavaria, Germany,