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bioRxiv · 10.1101/713222

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

Kikuchi, M.·Sekiya, M.·Hara, N.·Miyashita, A.·Kuwano, R.·Ikeuchi, T.·Iijima, K. M.·Nakaya, A.
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Abstract

The molecular biological mechanisms of Alzheimers disease (AD) involve disease-associated cross-talk 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 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 upregulated 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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Kikuchi, M., Sekiya, M., Hara, N., Miyashita, A., Kuwano, R., Ikeuchi, T., Iijima, K. M., Nakaya, A.. 2019-07-24. Disruption of a RAC1-centred protein interaction network is associated with Alzheimer’s disease pathology and causes age-dependent neurodegeneration. https://doi.org/10.1101/713222

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