Drosophila Atlastin regulates the stability of muscle microtubules and is required for synapse development (original) (raw)
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Current Biology, 2004
Development Hereditary Spastic Paraplegia (HSP) disease causes Vanderbilt University dysfunction in the corticospinal tract, causing progres-Nashville, Tennessee 37235 sive weakness and spasticity in the lower extremities 2 Department of Pharmacology [1]. The age of HSP onset ranges from the first to the Dulbecco Telethon Institute sixth decade, and symptoms also range widely in HSP Fondazione Telethon patients, making clinical data difficult to interpret. HSP University of Padova inheritance has been linked to at least 20 genetic loci [1], Padova, 35131 but less than half of these genes have been molecularly Italy identified. The characterized HSP-linked genes encode 3 Eugenio Medea Scientific Institute a diverse range of products, including cell adhesion Conegliano Research Center molecules (L1-CAM [2]), myelination proteins (DM20, Conegliano, 31015 PLP [3]), and microtubule motor proteins (KIF5A; [4]). Italy However, approximately 40% of HSP disease cases are linked to mutations of the SPG4 locus, which encodes Spastin [5, 6]. Spastin is an ATPase that contains a Summary microtubule-interacting domain [7], suggesting an active role in cytoskeleton interactions. Interestingly, a Background: Hereditary Spastic Paraplegia (
PLoS ONE, 2013
Axonal transport, a form of long-distance, bi-directional intracellular transport that occurs between the cell body and synaptic terminal, is critical in maintaining the function and viability of neurons. We have identified a requirement for the stathmin (stai) gene in the maintenance of axonal microtubules and regulation of axonal transport in Drosophila. The stai gene encodes a cytosolic phosphoprotein that regulates microtubule dynamics by partitioning tubulin dimers between pools of soluble tubulin and polymerized microtubules, and by directly binding to microtubules and promoting depolymerization. Analysis of stai function in Drosophila, which has a single stai gene, circumvents potential complications with studies performed in vertebrate systems in which mutant phenotypes may be compensated by genetic redundancy of other members of the stai gene family. This has allowed us to identify an essential function for stai in the maintenance of the integrity of axonal microtubules. In addition to the severe disruption in the abundance and architecture of microtubules in the axons of stai mutant Drosophila, we also observe additional neurological phenotypes associated with loss of stai function including a posterior paralysis and tail-flip phenotype in third instar larvae, aberrant accumulation of transported membranous organelles in stai deficient axons, a progressive bang-sensitive response to mechanical stimulation reminiscent of the class of Drosophila mutants used to model human epileptic seizures, and a reduced adult lifespan. Reductions in the levels of Kinesin-1, the primary anterograde motor in axonal transport, enhance these phenotypes. Collectively, our results indicate that stai has an important role in neuronal function, likely through the maintenance of microtubule integrity in the axons of nerves of the peripheral nervous system necessary to support and sustain long-distance axonal transport.
Drosophila Spastin Regulates Synaptic Microtubule Networks and Is Required for Normal Motor Function
PLOS Biology, 2004
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.
Drosophila melanogaster - Model for Recent Advances in Genetics and Therapeutics, 2018
Neuropathy target esterase (NTE) is a molecular target for the organophosphorus compound-induced delayed neuropathy (OPIDN) and also one of the genetic factors responsible for the development of the hereditary spastic paraplegia (HSP), characterized by axon degeneration of motoneurons causing progressive lower-limb spastic paralysis. Both HSP and OPIDN are characterized by the distal axonopathy. The molecular mechanisms underlying the axonopathy involved in HSP and OPIDN are poorly understood. In order to have a better understanding of the mechanisms that NTE is involved in, we used one of the homologs, human NTE. Swiss cheese (sws) is a Drosophila melanogaster ortholog of NTE with 39% homology. Mutations in sws as it was shown before lead to age-dependent neurodegeneration, structure alteration of glia cells, and reduced insect life span. To study SWS functions, we used the system of the third-instar larval neuromuscular junctions of D. melanogaster. In this study, we show that mutations in sws (sws 1 and sws 76−1) and SWS knockdown alter neuromuscular junction's morphology and synaptic microtubules organization.
Drosophila Atlastin in motor neurons is required for locomotion and presynaptic function
Journal of Cell Science, 2017
Hereditary spastic paraplegias (HSP) are characterized by spasticity and weakness of the lower limbs that result from length-dependent axonopathy of the corticospinal tracts. atlastin, the second most common HSP gene, catalyzes homotypic membrane fusion of endoplasmic reticulum (ER) tubules. How defects in neuronal Atlastin contribute to axonal degeneration has not been explained satisfactorily. Using Drosophila we demonstrate that downregulation or overexpression of Atlastin in motor neurons result in decreased crawling speed and contraction frequency in larvae, while adult flies show progressive decline in climbing ability. Broad expression in the nervous system is required to rescue the atlastin-null Drosophila mutant (atl2) phenotype. Importantly, both spontaneous release and the reserve pool of synaptic vesicles are affected. Additionally, axonal secretory organelles are abnormally distributed, whereas presynaptic proteins diminish at terminals and accumulate in distal axons, p...
TDP-43 is an evolutionarily conserved RNA binding protein recently associated with the pathogenesis of different neurological diseases. At the moment, neither its physiological role in vivo nor the mechanisms that may lead to neurodegeneration are well known. Previously, we have shown that TDP-43 mutant flies presented locomotive alterations and structural defects at the neuromuscular junctions. We have now investigated the functional mechanism leading to these phenotypes by screening several factors known to be important for synaptic growth or bouton formation. As a result we found that alterations in the organization of synaptic microtubules correlate with reduced protein levels in the microtubule associated protein futsch/MAP1B. Moreover, we observed that TDP-43 physically interacts with futsch mRNA and that its RNA binding capacity is required to prevent futsch down regulation and synaptic defects.
The effects of ER morphology on synaptic structure and function in Drosophila melanogaster
Journal of cell science, 2016
Hereditary Spastic Paraplegia (HSP) is a set of genetic diseases caused by mutations in one of 72 genes that results in age-dependent corticospinal axon degeneration accompanied by spasticity and paralysis. Two genes implicated in HSPs encode proteins that regulate ER morphology. Atlastin (SPG3A) encodes an ER membrane fusion GTPase and Reticulon 2 (SPG12) helps shape ER tube formation. Here we use a new fluorescent ER marker to show that the ER within wildtype Drosophila motor nerve terminals forms a network of tubules that is fragmented and made diffuse by atl loss. atl or Rtnl1 loss decreases evoked transmitter release and increases arborization. Similarly to other HSP genes, atl inhibits bone morphogenetic protein (BMP) signaling, and loss of atl causes age-dependent locomotor deficits in adults. These results demonstrate a critical role for ER in neuronal function and identify mechanistic links between ER morphology, neuronal function, BMP signaling, and adult behavior.
Developmental Biology, 2000
Drosophila 3-tubulin is an essential isoform expressed during differentiation of many cell types in embryos and pupae. We report here that during pupal development transient 3 expression demarcates a unique subset of neurons in the developing adult visual system. 3 is coassembled into microtubules with 1, the sole -tubulin isoform in the permanent microtubule cytoskeleton of the adult eye and brain. Examination of 3 mutant phenotypes showed that 3 is required for axonal patterning and connectivity and for spatial positioning within the optic lobe. Comparison of the phenotypes of 3 mutations with those that result from disruption of the Hedgehog signaling pathway shows that 3 functions early in the establishment of the adult visual system. Our data support the hypothesis that 3 confers specialized properties on the microtubules into which it is incorporated. Thus a transient specialization of the microtubule cytoskeleton during differentiation of a specific subset of the neurons has permanent consequences for later cell function.