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, Bin Zhang

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

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.

Original languageEnglish
Article number5234
JournalNature Communications
Volume10
Issue number1
DOIs
StatePublished - 1 Dec 2019

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