The landscape of multiscale transcriptomic networks and key regulators in Parkinson’s disease

Qian Wang, Yuanxi Zhang, Minghui Wang, Won-Min Song, Qi Shen, Andrew McKenzie, Insup Choi, Xianxiao Zhou, Ping-Yue Pan, Zhenyu Yue () and Bin Zhang ()
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Qian Wang: Department of Neurology and Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai
Yuanxi Zhang: Department of Neurology and Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai
Minghui Wang: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai
Won-Min Song: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai
Qi Shen: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai
Andrew McKenzie: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai
Insup Choi: Department of Neurology and Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai
Xianxiao Zhou: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai
Ping-Yue Pan: Department of Neurology and Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai
Zhenyu Yue: Department of Neurology and Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai
Bin Zhang: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract Genetic and genomic studies have advanced our knowledge of inherited Parkinson’s disease (PD), however, the etiology and pathophysiology of idiopathic PD remain unclear. Herein, we perform a meta-analysis of 8 PD postmortem brain transcriptome studies by employing a multiscale network biology approach to delineate the gene-gene regulatory structures in the substantia nigra and determine key regulators of the PD transcriptomic networks. We identify STMN2, which encodes a stathmin family protein and is down-regulated in PD brains, as a key regulator functionally connected to known PD risk genes. Our network analysis predicts a function of human STMN2 in synaptic trafficking, which is validated in Stmn2-knockdown mouse dopaminergic neurons. Stmn2 reduction in the mouse midbrain causes dopaminergic neuron degeneration, phosphorylated α-synuclein elevation, and locomotor deficits. Our integrative analysis not only begins to elucidate the global landscape of PD transcriptomic networks but also pinpoints potential key regulators of PD pathogenic pathways.

Date: 2019
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DOI: 10.1038/s41467-019-13144-y

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