ALS2 encodes alsin, a 184-kDa multi-domain protein functioning as a guanine nucleotide exchange factor (GEF) for the small GTPase Rab5 1. The protein contains three GEF domains (RCC1-like, DH/PH, and VPS9) and eight MORN motifs, enabling activation of Rab5 and regulation of endosomal trafficking and membrane dynamics 2. ALS2 promotes neurite outgrowth and protects motor neurons against excitotoxicity and oxidative stress through Rac1/phosphatidylinositol-3 kinase/Akt3 signaling pathways 3. Loss-of-function ALS2 mutations cause three related motor neuron diseases: infantile-onset ascending hereditary spastic paralysis (IAHSP), juvenile primary lateral sclerosis (JPLS), and juvenile amyotrophic lateral sclerosis (JALS), characterized by progressive degeneration of upper motor neurons 4. Most disease-causing mutations are premature termination variants resulting in loss of ALS2 function 1. Mechanistically, ALS2 dysfunction impairs endosomal trafficking and lysosomal biogenesis, representing a broader convergence point in ALS pathogenesis alongside other vesicle trafficking genes 5. Clinically, ALS2 mutations represent rare autosomal recessive disorders with insidious onset progressive spastic paraparesis, contractures, and dysarthria 4. Understanding ALS2's role in vesicle trafficking and motor neuron survival has therapeutic implications for broader ALS spectrum disorders.