Network Analysis and Human Single Cell Brain Transcriptomics Reveal Novel Aspects of Alpha-Synuclein (SNCA) Biology

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.

doi:10.1101/2020.06.05.137166

bioRxiv · 10.1101/2020.06.05.137166

Network Analysis and Human Single Cell Brain Transcriptomics Reveal Novel Aspects of Alpha-Synuclein (SNCA) Biology

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.

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Abstract

Alpha-synuclein (SNCA) aggregates are pathological hallmarks of synucleinopathies, neurodegenerative disorders including Parkinsons 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 < 10-10) 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 100kb. 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 expression.

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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.. 2020-06-08. Network Analysis and Human Single Cell Brain Transcriptomics Reveal Novel Aspects of Alpha-Synuclein (SNCA) Biology. https://doi.org/10.1101/2020.06.05.137166

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