Abstract TP283: The Emerging Role of Alpha-Synuclein in Stroke and Vascular Pathology

Introduction: Ischemic stroke involves a complex pathophysiology encompassing both neuronal and vascular components. Alpha-synuclein ( SNCA ), widely recognized for its role in neurodegenerative diseases such as Parkinson’s disease, has recently emerged as a potential contributor to vascular pathology and cancer. However, how SNCA is involved in the mechanisms behind stroke development and progression remain unclear. Transcriptomic studies have suggested that SNCA may exert neuroprotective effects, as music upregulated SNCA expression in individuals with high-music aptitude and in donors with cognitive disorders. Furthermore, increased SNCA expression in glioblastoma multiforme (GBM) was found to reduce tumor growth, indicating that SNCA expression may be beneficial in specific disease contexts. Methods: To elucidate SNCA ’s role in cerebrovascular pathologies, we compared changes in gene expression across three disease models, vascular injury (10.1109/TMBMC.2024.3501576) and ischemic stroke (GSE137482) in mouse, and GBM in human (GSE10878). Results: We observed consistent downregulation of SNCA in pathological conditions. Among differentially expressed genes (DEGs), 223 were uniquely shared between GBM and stroke and were associated with synapse organization and nervous system development. A larger set of 927 DEGs were exclusively identified between vascular injury and stroke, while 129 DEGs were commonly shared across three datasets. Gene Ontology analysis of these DEGs revealed significant enrichment in cell cycle-related terms. We further constructed a protein-protein interaction network and found that SNCA is directly involved in stress response and immune system regulation. Using Ingenuity Pathway Analysis, we predicted pathways involving SNCA , DEGs associated with cell cycling and immune system functions, and potential intermediate modulators. In the cell cycle network, SNCA inhibition was predicted to upregulate CCNA2 through STAT3 and KLF4, suggesting a potential regulatory mechanism in stroke. In the immune system network, SNCA may modulate VCAM1 and CD44 via CAV1 and IL6 . Conclusion: These findings indicate that SNCA has the potential to act as a global regulator of cellular functions and highlight its promise as a therapeutic target for cerebrovascular diseases and GBM. *KP and GB contributed equally to this work