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.
Highlights
Genetic and genomic studies have advanced our knowledge of inherited Parkinson’s disease (PD), the etiology and pathophysiology of idiopathic PD remain unclear
As the central nervous system (CNS) is composed of multiple types of cells with distinct contributions to PD pathogenesis and progression, we examined the cell-type specificity of the modules using the gene signatures of six major brain cell types, including neurons, astrocytes, microglia, endothelial cells, oligodendrocyte precursor cells (OPC), and oligodendrocytes generated from the human brain[33,34] (Fig. 1d; Supplementary Data 6)
After mapping mouse genes to the human homologues, we found a significant overlap between the genes positively correlated with STMN2 in PD patients and those downregulated in Stmn[2] knockdown mice and between the genes negatively correlated with STMN2 in the PD patients and the genes upregulated in Stmn[2] knockdown mice
Summary
Genetic and genomic studies have advanced our knowledge of inherited Parkinson’s disease (PD), the etiology and pathophysiology of idiopathic PD remain unclear. Our previous study integrated large-scale genetic and gene expression data as well as clinical and pathological traits into multiscale network models of Alzheimer’s disease (AD)[16], and several predicted key regulators of AD pathogenesis such as TYROBP, DTL/CDT2, and GJA1 were subsequently validated in various model systems[24,25,26,27]. Such network biology approaches have not been applied to PD research yet due to the lack of molecular profiling data from a large number of postmortem brain samples. The network models shed a light on the global landscape of molecular interactions and regulations in PD and reveal detailed circuits and potential key regulators of PD pathogenic pathways for further experimental investigation
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