Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.05.137166v1?rss=1 Authors: Teeple, E., Jindal, K., Kiragasi, B., Annaldasula, S., Byrne, A., Chai, L., Sadeghi, M., Kayatekin, C., Shankara, S., Klinger, K., Sardi, S. P., Madden, S. L., Kumar, D. Abstract: Alpha-synuclein(SNCA) aggregates are pathological hallmarks of synucleinopathies, neurodegenerative disorders including Parkinson's Disease (PD) and Lewy Body Dementia (LBD). Functional networks are not yet well-characterized for SNCA by CNS cell type. We investigated cell-specific differences in SNCA expression using Allen Brain Database single-nucleus RNA-seq data from human Middle Temporal Gyrus (MTG, 15,928 nuclei) and Anterior Cingulate Cortex (ACC, 7,258 nuclei). Weighted gene co-expression analysis (WGCNA) and hierarchical clustering identified a conserved SNCA co-expression module. Module genes were highly conserved (p<10e-10) and most highly expressed in excitatory neurons versus inhibitory neurons and other glial cells. SNCA co-expression module genes from ACC and MTG regions were then used to construct a protein-protein interaction (PPI) network, with SNCA empirically top hub. Genes in the SNCA PPI network were compared with genes nearest single nucleotide polymorphisms linked with PD risk in genome-wide association studies. 16 genes in our PPI network are nearest genes to PD risk loci (p<0.0006) and 55 genes map within 100 kb. Selected SNCA PPI network genes nearest PD risk loci were disrupted by CRISPR knock out gene editing for validation of network functional significance; disruption of STK39, GBA, and MBNL2 resulted in significantly elevated intracellular SNCA protein expression Copy rights belong to original authors. Visit the link for more info