Meta-Analysis of Parkinson’s Disease and Alzheimer’s Disease Revealed Commonly Impaired Pathways and Dysregulation of NRF2-Dependent Genes

Article type: Research Article

Authors: Wang, Qian^{a; b; 1} | Li, Wen-Xing^{a; c; 1} | Dai, Shao-Xing^{a; b} | Guo, Yi-Cheng^a | Han, Fei-Fei^d | Zheng, Jun-Juan^{a; b} | Li, Gong-Hua^{a; b; *} | Huang, Jing-Fei^{a; b; e; f; g; *}

Affiliations: [a] State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China | [b] Kunming College of Life Science, University of Chinese Academy of Sciences, Beijing, China | [c] Institute of Health Sciences, Anhui University, Hefei, Anhui, China | [d] Immuno-Metabolic Computational Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA | [e] KIZ-SU Joint Laboratory of Animal Models and Drug Development, College of Pharmaceutical Sciences, Soochow University, Kunming, Yunnan, China | [f] Collaborative Innovation Center for Natural Products and Biological Drugs of Yunnan, Kunming, Yunnan, China | [g] Chinese University of Hong Kong Joint Research Center for Bio-resources and Human Disease Mechanisms, Kunming, Yunnan, China

Correspondence: [*] Correspondence to: Gong-Hua Li and Jing-Fei Huang, State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, Yunnan, China. Tel.: +86 0871 65199200; Fax: +86 0871 65199200; E-mails: [email protected] (G.-H Li); [email protected](J.-F Huang).

Note: [1] These authors contributed equally to this work.

Abstract: Many lines of evidence suggest that Parkinson’s disease (PD) and Alzheimer’s disease (AD) have common characteristics, such as mitochondrial dysfunction and oxidative stress. As the underlying molecular mechanisms are unclear, we perform a meta-analysis with 9 microarray datasets of PD studies and 7 of AD studies to explore it. Functional enrichment analysis revealed that PD and AD both showed dysfunction in the synaptic vesicle cycle, GABAergic synapses, phagosomes, oxidative phosphorylation, and TCA cycle pathways, and AD had more enriched genes. Comparing the differentially expressed genes between AD and PD, we identified 54 common genes shared by more than six tissues. Among them, 31 downregulated genes contained the antioxidant response element (ARE) consensus sequence bound by NRF2. NRF2 is a transcription factor, which protects cells against oxidative stress through coordinated upregulation of ARE-driven genes. To our surprise, although NRF2 was upregulated, its target genes were all downregulated. Further exploration found that MAFF was upregulated in all tissues and significantly negatively correlated with the 31 NRF2-dependent genes in diseased conditions. Previous studies have demonstrated over-expressed small MAFs can form homodimers and act as transcriptional repressors. Therefore, MAFF might play an important role in dysfunction of NRF2 regulatory network in PD and AD.

Keywords: Parkinson’s disease, Alzheimer’s disease, meta-analysis, MAFF, NRF2

DOI: 10.3233/JAD-161032

Journal: Journal of Alzheimer's Disease, vol. 56, no. 4, pp. 1525-1539, 2017