LRRK2 has been implicated in a variety of cellular processes, including autophagy 4, mitochondrial function 5, and vesicular trafficking 6. For example, SNCA has been reported to be localized at presynapse through lipid-raft binding 2 and play a role in vesicular trafficking 3. 1 and MDS Taskforce database: Tremendous effort has been made to characterize the functions of these genes. Previous research has identified over 20 PD causal mutations in SNCA, LRRK2, VPS35, PINK1, DJ-1, Parkin, FBXO7, DNAJC6, ATP13A2, DCTN1, and SYNJ1 (for review, see ref. Parkinson’s disease (PD) is a common neurodegenerative disorder characterized pathologically by the loss of dopaminergic (DA, or tyrosine hydroxylase positive, TH+) neurons in the substantia nigra (SN) and the presence of Lewy bodies and Lewy neurites in affected brain regions. 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. Stmn2 reduction in the mouse midbrain causes dopaminergic neuron degeneration, phosphorylated α-synuclein elevation, and locomotor deficits. Our network analysis predicts a function of human STMN2 in synaptic trafficking, which is validated in Stmn2-knockdown mouse dopaminergic neurons. 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. 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. Genetic and genomic studies have advanced our knowledge of inherited Parkinson’s disease (PD), however, the etiology and pathophysiology of idiopathic PD remain unclear.
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