Septins in the nervous system: from cytoskeletal dynamics to neurological disorders

Abstract Septins are GTP-binding cytoskeletal proteins primarily known to be involved in cell division, membrane remodeling, and cytoskeletal organization. In the nervous system, septins are suggested as key regulators of neural development, including neurite outgrowth, spine morphology, and axon initial segment formation. Septins are localized to specialized membrane domains, such as dendritic spines, axon initial segments, and synaptic terminals, where they function as scaffolding components and diffusion barriers. They are abundant in neurons, oligodendrocytes, Schwann cells, and astrocytes, regulating processes like myelination and synaptic organization. In neuronal cells, specific septin isoforms such as SEPT3, SEPT5, and SEPT7 contribute to dendritic spine formation, neurotransmitter vesicle trafficking, and axonal integrity. Alterations in septin expression or assembly can disrupt synaptic architecture and neuroplasticity, emphasizing their role in neuronal homeostasis. Dysregulation of septin expression and function has been implicated in a range of neurological disorders, including demyelinating diseases like Multiple Sclerosis and Hereditary Neuralgic Amyotrophy. Abnormal septin aggregation has been observed in neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Moreover, septins can modulate inflammatory responses, where antibodies for septins 5 and 7 were associated with autoimmune encephalitis conditions. This review will provide a comprehensive overview of the role of septins in the nervous system, focusing on their molecular mechanisms, cellular functions, and implications in neurological disorders.