[HTML][HTML] Drosophila Spastin Regulates Synaptic Microtubule Networks and Is Required for Normal Motor Function

NT Sherwood, Q Sun, M Xue, B Zhang, K Zinn - PLoS biology, 2004 - journals.plos.org
NT Sherwood, Q Sun, M Xue, B Zhang, K Zinn
PLoS biology, 2004journals.plos.org
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. Patients with AD-
HSP exhibit degeneration of the distal regions of the longest axons in the spinal cord. Loss-
of-function mutations in the Drosophila spastin gene produce larval neuromuscular junction
(NMJ) phenotypes. NMJ synaptic boutons in spastin mutants are more numerous and more …
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. Patients with AD-HSP exhibit degeneration of the distal regions of the longest axons in the spinal cord. Loss-of-function mutations in the Drosophila spastin gene produce larval neuromuscular junction (NMJ) phenotypes. NMJ synaptic boutons in spastin mutants are more numerous and more clustered than in wild-type, and transmitter release is impaired. spastin-null adult flies have severe movement defects. They do not fly or jump, they climb poorly, and they have short lifespans. spastin hypomorphs have weaker behavioral phenotypes. Overexpression of Spastin erases the muscle microtubule network. This gain-of-function phenotype is consistent with the hypothesis that Spastin has microtubule-severing activity, and implies that spastin loss-of-function mutants should have an increased number of microtubules. Surprisingly, however, we observed the opposite phenotype: in spastin-null mutants, there are fewer microtubule bundles within the NMJ, especially in its distal boutons. 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.
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