Abstract B010: α-Synuclein preformed fibrils suppress cell cycle progression and glycolytic flux in glioblastoma cells

Abstract Aging-related diseases, including cancer and neurodegenerative disorders, exhibit complex interrelationships. While Parkinson's disease (PD) and glioblastoma (GBM) both affect the central nervous system, they are pathophysiologically distinct, with an inverse correlation in their incidence. However, the mechanisms underlying this inverse relationship remain poorly understood. Here, we investigate the effects of α-synuclein preformed fibrils (PFF) on GBM cells to explore potential link between neurodegenerative diseases and malignancies. α-synuclein PFF are in vitro–assembled fibrils derived from recombinant monomeric α-synuclein, which recapitulate key pathological features of Lewy body inclusions and have been widely used to model synucleinopathies. In this study, we utilized two GBM cell lines to examine the cellular response against proteopathic PFF. PFF exerted anti-tumor activity through cyclin D1 downregulation, leading to G1 cell cycle arrest. Notably, PFF treatment significantly reduced glycolytic flux while sparing mitochondrial oxidative phosphorylation, indicating selective metabolic disruption. Furthermore, PFF inhibited the AKT signaling pathway, resulting in FOXO1 upregulation, which further contributed to its anti-tumor effects. Our findings provide novel insights into the metabolic and molecular implications of α-synuclein aggregation in GBM, suggesting a potential mechanistic link between neurodegenerative disease processes and tumor suppression, as well as therapeutic potential for cancer treatment. Citation Format: Hyo-Jin Song, Hyeon Ji Kim, Bo Kyung Joo, Jin-Seok Byun, Do-Yeon Kim. α-Synuclein preformed fibrils suppress cell cycle progression and glycolytic flux in glioblastoma cells [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Mechanisms of Cancer Immunity and Cancer-related Autoimmunity; 2025 Sep 24-27; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(9 Suppl):Abstract nr B010.