| Autor: |
Srinivas Shankara, Stephen L. Madden, Erin Teeple, Khushboo Jindal, S. Pablo Sardi, Beril Kiragasi, Can Kayatekin, Siddharth Annaldasula, Dinesh Kumar, Ann Byrne, Klinger Kw, Lilly Chai, Mahdiar Sadeghi |
| Rok vydání: |
2020 |
| Předmět: |
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| DOI: |
10.1101/2020.06.05.137166 |
| Popis: |
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 < 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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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