α-synuclein preformed fibrils suppress cell cycle progression and glycolytic flux in glioblastoma cells.

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, 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. 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 impacts of α-synuclein aggregation on GBM, offering a potential mechanistic link between neurodegenerative processes and tumor suppression.