SMCR8 is a critical component of the C9orf72-SMCR8 complex, which functions as a GTPase-activating protein (GAP) with multiple roles in cellular homeostasis 1. Within the complex, SMCR8 serves as the catalytic GAP subunit while C9orf72 acts as the substrate-binding subunit, together promoting GTPase activity of RAB8A and RAB39B to facilitate autophagosome maturation and membrane trafficking 2. SMCR8 also functions as a negative regulator of autophagy initiation by inhibiting ULK1/ATG1 kinase activity and suppressing expression of autophagy genes including ULK1 and WIPI2 3. Additionally, the C9orf72-SMCR8 complex negatively regulates primary ciliogenesis through RAB8A GAP activity, with implications for hedgehog signaling 1. SMCR8 stability depends on C9orf72 binding; in its absence, SMCR8 undergoes rapid proteasomal degradation via UBR5-mediated K11/K48-linked ubiquitination 4. Loss or reduction of SMCR8 impairs autophagy-lysosomal function and axonal transport, causing motor deficits and axonal swellings 5. These functions are particularly relevant to C9orf72-related amyotrophic lateral sclerosis and frontotemporal dementia, where hexanucleotide repeat expansions cause SMCR8 downregulation, exacerbating neurodegeneration 56.