Spastin Is Required to Prevent SPAST ‐Related Demyelination
Mutations in the
SPAST
gene, encoding the microtubule‐severing protein Spastin, cause the most common type of hereditary spastic paraplegia (HSP): SPG4, a disorder primarily characterized by length‐dependent axonal degeneration. Clinically, most SPG4 patients present with a pure phenotype marked by progressive spasticity in the lower extremities. It has also been reported that complex cases exhibit demyelination and cognitive deficits. Additionally, some
SPAST
variants have been determined in patients with multiple sclerosis (MS), indicating potential shared pathological mechanisms. Spastin is known to promote axonal regeneration by remodeling microtubules, whereas mutant Spastin disrupts microtubule dynamics and causes axonal transport defects in SPG4. However, whether Spastin dysfunction impairs regenerative processes such as myelination remains unknown. In this study, we investigated whether the SPG4‐associated
SPAST
mutations affect axonal myelination. Using an in vitro cortical neuron‐oligodendrocyte co‐culture model, we found that pathogenic
SPAST
mutations result in a significant reduction in the myelination index. Furthermore, a cuprizone‐induced demyelination mouse model revealed a decrease in Spastin protein levels in demyelinated white matter. Given Spastin's role in axonal regeneration, we hypothesized that Spastin may also protect against demyelination. Supporting this, wild‐type Spastin expression protected neurons from demyelination in a cuprizone‐induced cell culture demyelination model. Together, these results suggest a role for Spastin in axonal myelination, and its dysfunction may compromise myelin stability. Our findings highlight that impaired myelin stability may represent a secondary pathological feature of SPG4, contributing to disease complexity. This dual role of Spastin in axonal maintenance and myelin stability suggests its potential relevance for contributing to complex forms of SPG4.
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Torben J. Hausrat, Jennifer Radwitz, Franco L. Lombino et al.
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- Published
- Mar 01, 2026
- Vol/Issue
- 170(3)
- License
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