The Global Landscape of Multiscale Transcriptomic Networks and Key Regulators in Parkinson’s Disease

Despite the advance of genetic and genomic analysis of Parkinson’s disease (PD), our understanding of PD pathophysiology remains limited due to unclear etiology of idiopathic PD and unavailable integrated approach for large-scale multi-dimensional data. Herein we report a novel multiscale network approach to establish transcriptomic network from postmortem PD brain data. The analysis delineates structures of gene-gene regulatory networks in PD and identifies novel network regulators that are functionally connected to previously identified PD risk genes. We identify STMN2, encoding a neuron-specific stathmin family protein and down-regulated in PD brains, as the top regulator of the transcriptomic network underlying PD. Knock-down of Stmn2 in mice validates its regulatory role, and Stmn2 deficient mice show dopaminergic neuron vulnerability, phosphorylated a-synuclein elevation, and locomotor function deficits. As predicted from the network analysis, reduced STMN2 expression impairs synaptic vesicle trafficking in midbrain neurons. Our approach sheds light on the complexity of PD pathogenic network and thus facilitates identification of novel PD therapeutic targets. AAV that carries Stmn2 shRNA or scrambled control shRNA was injected into the midbrain in 2 month old male C57BL/6J mice unilaterally. After 30 days, mice were sacrificed and the infected midbrain tissue were isolated and total RNA was extracted using Qiagen RNeasy mini kit. 3 controls and 4 knockdown samples were sequenced and analyzed