INA (internexin neuronal intermediate filament protein alpha) is a Class-IV neuronal intermediate filament protein that plays a critical role in neuronal morphogenesis and cytoskeletal organization. INA functions as a structural component that can self-assemble to form independent filamentous networks or cooperate with other neurofilament proteins (NEFL, NEFM, NEFH) to form the structural backbone of the postsynaptic intermediate filament cytoskeleton. INA participates in substantia nigra development and intermediate filament organization. INA stability and homeostasis are regulated by the CRL3GIG-USP15 ubiquitin-proteasome pathway, where gigaxonin (GIG) targets INA for proteasomal degradation via a specific NEFLL12 degron 1. Mutations in GAN gene encoding gigaxonin disrupt INA binding and cause its pathological accumulation in axons, leading to giant axonal neuropathy (GAN). Beyond neurofilament regulation, this pathway also controls actin filament dynamics through targeting actin-binding regulatory proteins 1. Clinically, INA dysfunction is associated with neurodegenerative conditions. INA interacts with the NMDA receptor through the GCOM1 complex, suggesting involvement in neuroprotective pathways 2. These protein-protein interactions implicate INA in synaptic function and neurologic disease mechanisms. Understanding INA regulation offers therapeutic opportunities for treating GAN and related neurodegenerative diseases by modulating CRL3GIG substrate targeting.