Functional Characterization of Spastin and its Role in Hereditary Spastic Paraplegia

Errico, Alessia (2004). Functional Characterization of Spastin and its Role in Hereditary Spastic Paraplegia. PhD thesis The Open University.



Hereditary spastic paraplegia (HSP) is a neurodegenerative disease characterized by the spasticity of the lower limbs due to degeneration of the corticospinal tracts. The gene responsible for the most frequent form of autosomal dominant HSP encodes spastin, an ATPase belonging to the AAA family.
Studies with specific antibodies indicate that spastin has both a nuclear and cytosolic localization. In human fibroblasts spastin localizes to the PML bodies, but is also present on the centrosome. In HeLa and Cos? cells, during mitosis, spastin is enriched in regions rich in microtubules, like the spindle poles and the midbody. Furthermore, in an immortalized motoneuronal cell line, spastin is detected in the growth cone of the axons. By overexpressing wild-type or ATPase-defective spastin, we show that spastin interacts dynamically with microtubules. This association is mediated by the N-terminal region of the protein and regulated through its ATPase activity. The overexpression of wild-type spastin promotes microtubule disassembly; leading to the hypothesis that spastin may play a role in microtubule dynamics.
We identify Spastin nuclear and centrosomal interactors, reflecting the complex subcellular localization of the protein. We demonstrate that Spastin interacts with Daxx, a transcriptional regulator, and that the overexpression of Daxx causes an increase of spastin transcript, suggesting that Spastin may play a role in regulation of transcription. We show that spastin is sumoylated, although the function of this modification is unclear. Moreover, Spastin interacts with a centrosomal protein. Nal4, and we postulate that this protein may represent the anchor for spastin to bind centrosomes and microtubules.
All these data suggest that spastin has a complex role in the cell and may contribute in different ways to the integrity of corticospinal axons. Spastin localization to the neurites and its dynamic association with microtubules let us hypothesise that a defect in axonal transport may underlie HSP.

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