Disease relevance of spas

• The Drosophila homologue of the hereditary spastic paraplegia protein, spastin, severs and disassembles microtubules [1].
• The human SPG4 locus encodes the spastin gene, which is responsible for the most prevalent form of autosomal dominant hereditary spastic paraplegia (AD-HSP), a neurodegenerative disorder [2].

High impact information on spas

• At the subcellular level, neuronal expression of both Dspastin RNA interference and mutant Dspastin cause an excessive stabilization of microtubules in the neuromuscular junction synapse [3].
• Furthermore, its Drosophila homolog, Drosophila spastin (Dspastin), has been recently shown to regulate microtubule stability and synaptic function at the Drosophila larval neuromuscular junction [3].
• CONCLUSIONS: Loss of Dspastin in Drosophila causes an aberrantly stabilized microtubule cytoskeleton in neurons and defects in synaptic growth and neurotransmission [4].
• During embryogenesis, the expression pattern of Drosophila spastin becomes restricted primarily to the central nervous system, in contrast to the ubiquitous expression of the vertebrate spastin genes [2].
• Here we identify the predicted gene product CG5977 as the Drosophila homolog of the human spastin gene, with much higher sequence similarities than any other related AAA domain protein in the fly [2].

Biological context of spas

• RESULTS: Employing Drosophila transgenic methods for overexpression and RNA interference (RNAi), we have investigated the role of Spastin in vivo [4].
• They do not fly or jump, they climb poorly, and they have short lifespans. spastin hypomorphs have weaker behavioral phenotypes [5].

Anatomical context of spas

• Functional synaptic defects caused by Dspastin RNAi and overexpression were pharmacologically alleviated by agents that destabilize and stabilize microtubules, respectively [4].
• At neuromuscular junctions (NMJ), Dspastin RNAi causes morphological undergrowth and reduced synaptic area [4].
• The Drosophila NMJ is a glutamatergic synapse that resembles excitatory synapses in the mammalian spinal cord, so the reduction of organized presynaptic microtubules that we observe in spastin mutants may be relevant to an understanding of human Spastin's role in maintenance of axon terminals in the spinal cord [5].

Other interactions of spas

• The most common form of human autosomal dominant hereditary spastic paraplegia (AD-HSP) is caused by mutations in the SPG4 (spastin) gene, which encodes an AAA ATPase closely related in sequence to the microtubule-severing protein Katanin [5].

Analytical, diagnostic and therapeutic context of spas

• Previous work in cell culture has proposed a role for Spastin in regulating microtubules [4].
• Here we report the generation of a spastin-linked HSP animal model and show that in Drosophila, neural knockdown of Dspastin and, conversely, neural overexpression of Dspastin containing a conserved pathogenic mutation both recapitulate some phenotypic aspects of the human disease, including adult onset, locomotor impairment, and neurodegeneration [3].

References