Disruption of a RAC1-centred network is associated with Alzheimer’s disease pathology and causes age-dependent neurodegeneration

Kikuchi, Masataka; Sekiya, Michiko; Hara, Norikazu; Miyashita, Akinori; Kuwano, Ryozo; Ikeuchi, Takeshi; Iijima, Koichi M.; Nakaya, Akihiro

doi:10.1093/hmg/ddz320

Title: Disruption of a RAC1-centred network is associated with Alzheimer’s disease pathology and causes age-dependent neurodegeneration

Journal Article · Thu Jan 16 00:00:00 EST 2020 · Human Molecular Genetics

DOI:https://doi.org/10.1093/hmg/ddz320· OSTI ID:1607604

Kikuchi, Masataka ^[1]; Sekiya, Michiko ^[2]; Hara, Norikazu ^[3]; Miyashita, Akinori ^[3]; Kuwano, Ryozo ^[4]; Ikeuchi, Takeshi ^[3]; Iijima, Koichi M. ^[2]; Nakaya, Akihiro ^[1]

Department of Genome Informatics, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
Department of Alzheimer’s Disease Research, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Aichi 474-8511, Japan, Department of Experimental Gerontology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Aichi 467-8603, Japan
Department of Molecular Genetics, Brain Research Institute, Niigata University, Niigata 951-8585, Japan
Department of Molecular Genetics, Brain Research Institute, Niigata University, Niigata 951-8585, Japan, Asahigawaso Medical-Welfare Center, Asahigawaso Research Institute, Okayama 703-8207, Japan

Abstract The molecular biological mechanisms of Alzheimer’s disease (AD) involve disease-associated crosstalk through many genes and include a loss of normal as well as a gain of abnormal interactions among genes. A protein domain network (PDN) is a collection of physical bindings that occur between protein domains, and the states of the PDNs in patients with AD are likely to be perturbed compared to those in normal healthy individuals. To identify PDN changes that cause neurodegeneration, we analysed the PDNs that occur among genes co-expressed in each of three brain regions at each stage of AD. Our analysis revealed that the PDNs collapsed with the progression of AD stage and identified five hub genes, including Rac1, as key players in PDN collapse. Using publicly available as well as our own gene expression data, we confirmed that the mRNA expression level of the RAC1 gene was downregulated in the entorhinal cortex (EC) of AD brains. To test the causality of these changes in neurodegeneration, we utilized Drosophila as a genetic model and found that modest knockdown of Rac1 in neurons was sufficient to cause age-dependent behavioural deficits and neurodegeneration. Finally, we identified a microRNA, hsa-miR-101-3p, as a potential regulator of RAC1 in AD brains. As the Braak neurofibrillary tangle (NFT) stage progressed, the expression levels of hsa-miR-101-3p were increased specifically in the EC. Furthermore, overexpression of hsa-miR-101-3p in the human neuronal cell line SH-SY5Y caused RAC1 downregulation. These results highlight the utility of our integrated network approach for identifying causal changes leading to neurodegeneration in AD.

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Sponsoring Organization:: USDOE Office of Electricity (OE), Advanced Grid Research & Development. Power Systems Engineering Research

OSTI ID:: 1607604

Alternate ID(s):: OSTI ID: 1599912

Journal Information:: Human Molecular Genetics, Journal Name: Human Molecular Genetics Vol. 29 Journal Issue: 5; ISSN 0964-6906

Publisher:: Oxford University PressCopyright Statement

Country of Publication:: United Kingdom

Language:: English

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Cited by: 13 works

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