The hereditary spastic paraplegia gene, spastin, regulates microtubule stability to modulate synaptic structure and function

Nick Trotta, Genny Orso, Maria Giovanna Rossetto, Andrea Daga, Kendal Broadie

Research output: Contribution to journalArticlepeer-review


Background: Hereditary Spastic Paraplegia (HSP) is a devastating neurological disease causing spastic weakness of the lower extremities and eventual axonal degeneration. Over 20 genes have been linked to HSP in humans; however, mutations in one gene, spastin (SPG4), are the cause of >40% of all cases. Spastin is a member of the ATPases associated with diverse cellular activities (AAA) protein family, and contains a microtubule interacting and organelle transport (MIT) domain. Previous work in cell culture has proposed a role for Spastin in regulating microtubules. Results: Employing Drosophila transgenic methods for overexpression and RNA interference (RNAi), we have investigated the role of Spastin in vivo. We show that Drosophila Spastin (D-Spastin) is enriched in axons and synaptic connections. At neuromuscular junctions (NMJ), Dspastin RNAi causes morphological undergrowth and reduced synaptic area. Moreover, Dspastin overexpression reduces synaptic strength, whereas Dspastin RNAi elevates synaptic currents. By using antibodies against posttranslationally modified α-Tubulin, we find that Dspastin regulates microtubule stability. Functional synaptic defects caused by Dspastin RNAi and overexpression were pharmacologically alleviated by agents that destabilize and stabilize microtubules, respectively. Conclusions: Loss of Dspastin in Drosophila causes an aberrantly stabilized microtubule cytoskeleton in neurons and defects in synaptic growth and neurotransmission. These in vivo data strongly support previous reports, providing a probable cause for the neuronal dysfunction in spastin-linked HSP disease. The role of Spastin in regulating neuronal microtubule stability suggests therapeutic targets for HSP treatment and may provide insight into neurological disorders linked to microtubule dysfunction.

Original languageEnglish
Pages (from-to)1135-1147
Number of pages13
JournalCurrent Biology
Issue number13
Publication statusPublished - Jul 13 2004

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)


Dive into the research topics of 'The hereditary spastic paraplegia gene, spastin, regulates microtubule stability to modulate synaptic structure and function'. Together they form a unique fingerprint.

Cite this