Spastinen

Spastin, a term sometimes used as spastinen in certain languages, is a microtubule‑severing ATPase belonging to the AAA protein family. It is encoded by the SPG4 gene and is the most common genetic cause of hereditary spastic paraplegia (HSP). Mutations in SPG4 lead to degeneration of long corticospinal tract axons, resulting in progressive spasticity and weakness of the legs, often with later involvement of other movement or cognitive functions.

Spastin exists in multiple isoforms produced by alternative translation initiation, with two major forms commonly described: M1 and M87. The M1 isoform contains an N‑terminal hydrophobic region that targets the protein to the endoplasmic reticulum, while the M87 isoform lacks this segment. Both isoforms share the central ATPase domain that drives their enzymatic activity. Structurally, spastin forms hexamers in which ATP hydrolysis provides the energy to sever microtubules, a process important for regulating microtubule dynamics, organelle shaping, and aspects of membrane trafficking.

In cells, spastin participates in several pathways, including endosomal tubulation, ER morphology, and intracellular transport, all of which contribute to proper axonal maintenance. Disruption of spastin function impairs microtubule severing and can perturb intracellular trafficking, potentially contributing to neurodegeneration in HSP.

Clinical features of SPG4‑related HSP are highly variable, but typically include slowly progressive spastic paraplegia with leg‑dominant weakness, increased reflexes, and gait disturbances. Diagnosis is based on clinical presentation plus genetic testing for SPG4 mutations. Management focuses on symptom relief and physical therapy.