Spinocerebellar ataxia type 2 (SCA2) is a rare neurodegenerative disorder characterized by cerebellar dysfunction and significant loss of Purkinje cells, with subsequent involvement of other brain regions, suggesting a potential disease-spreading mechanism. Our study sheds light on SCA2 pathogenesis by revealing the presence of mutant ATXN2 mRNA within small extracellular vesicles (sEVs). These sEVs demonstrate the ability to transport the mutant mRNA to recipient cells, leading to its translation and the formation of mutant protein aggregates, a neuropathological hallmark of SCA2.Additionally, we observed a functional consequence of sEV-mediated spreading, evidenced by decreased muscular strength in wild-type mice injected with sEVs derived from SCA2 transgenic mouse brains. This highlights the significance of sEVs in disease progression, emphasizing the need for understanding the underlying mechanisms.RNA-binding proteins (RBPs) emerge as key players in this process, with 14 identified RBPs potentially involved in translocating ATXN2 into sEVs. Experimental validation implicates some RBPs in modulating ATXN2 levels within sEVs, suggesting their potential as therapeutic targets.Overall, our findings propose a novel paradigm wherein sEVs facilitate the spreading of mutant ATXN2 mRNA across the brain, contributing to SCA2 pathogenesis. By elucidating the molecular mechanisms, particularly focusing on RBPs, we aim to identify promising therapeutic targets for halting or delaying SCA2 progression. This comprehensive understanding of sEV-mediated disease spreading opens avenues for innovative therapeutic interventions not only in SCA2, but potentially in other neurodegenerative disorders as well.