UBQLN2 is a ubiquitin-binding quality control protein highly expressed in the nervous system and muscle that plays a critical role in protein homeostasis. It functions as a shuttle factor that targets misfolded or accumulated proteins for degradation by binding polyubiquitin chains via its UBA domain and interacting with proteasomal subunits 1. UBQLN2 operates across multiple degradation pathways: it mediates ubiquitin-proteasome system (UPS) targeting, participates in ER-associated protein degradation (ERAD) through interactions with ER-localized proteins, and regulates autophagy by promoting LC3-I to LC3-II maturation and autophagosome-lysosome fusion 23. Additionally, UBQLN2 negatively regulates GPCR endocytosis and is recruited to stress granules where it influences their disassembly kinetics 4. UBQLN2 is essential for mitochondrial protein degradation and turnover, processes critical for motor neuron survival 5. X-linked dominant mutations in UBQLN2 cause amyotrophic lateral sclerosis (ALS) with or without frontotemporal dementia (FTD), with males typically developing disease 18 years earlier than females 6. Disease pathogenesis involves failed protein degradation and dysregulated stress granule formation 7. UBQLN2 also regulates pathological α-synuclein degradation, suggesting broader relevance to neurodegenerative diseases beyond ALS/FTD 8.