ATXN2 encodes a polyglutamine-containing protein with pleiotropic functions in RNA metabolism, stress granule dynamics, and endocytosis 1. The protein negatively regulates EGFR internalization and plays critical roles in translation regulation and RNA binding. ATXN2 associates with TDP-43 in an RNA-dependent complex, modulating TDP-43 toxicity in neuronal cells 2. ATXN2 is primarily associated with spinocerebellar ataxia type 2 (SCA2) when CAG repeat expansions exceed 33 glutamines, causing toxic gain-of-function and/or partial loss-of-function through conformational changes 1. However, intermediate-length polyglutamine expansions (27-33 repeats) represent a significant ALS susceptibility locus, with exponential increases in disease risk for 29-32 repeats 23. This intermediate expansion mechanism differs from classic trinucleotide repeat diseases, as repeat length predicts ALS risk but not age of onset or survival 3. In SCA2 pathology, ATXN2 dysfunction impairs autophagy, elevates oxidative stress, disrupts calcium homeostasis, and promotes RNA-mediated toxicity 1. Therapeutically, ATXN2-targeting antisense oligonucleotides are currently in clinical trials for ALS 45, representing a promising approach for both familial and sporadic disease.