The Hereditary Spastic Paraplegia Gene, spastin, Regulates Microtubule Stability to Modulate Synaptic Structure and Function

Abstract

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.

In vivo assay of presynaptic microtubule cytoskeleton dynamics in Drosophila

“…Previous studies have made strong inferences about altered microtubule dynamics in different genetic mutants and disease models based wholly on very indirect assays of the local microtubule state within synapses (Zhang et al, 2001;Huot et al, 2001;McDermott et al, 2003;Lu et al, 2004;Sherwood et al, 2004;Trotta et al, 2004;Zhang and Broadie, 2005;Orso et al, 2005). The goal of this study was to develop techniques to directly assay microtubule dynamics, locally at synapses, in living neurons in situ.…”

“…We have previously proposed altered synaptic microtubule dynamics as a causative defect in Drosophila genetic models of Fragile X Syndrome (FXS) and Hereditary Spastic Paraplegia (HSP) (Zhang et al, 2001;Trotta et al, 2004;Zhang and Broadie 2005): FXS is caused by loss of function of the FMR1 gene, which encodes a negative translational regulator of Futsch/ microtubule associated protein 1B (MAP1B), and 40% of HSP cases are linked to mutations of the spastin gene, which encodes a microtubule severing protein. Indirect evidence suggests that synaptic microtubules are hyper-stabilized in both mutants, but several mechanisms could be responsible.…”

“…Microtubules are abundant throughout neurons and are known to be critical for the generation and maintenance of neuronal processes, including dendrites and axons, transport along these exceptionally elongated, polarized processes, and the development and maintenance of synaptic transmission in both pre-and postsynaptic compartments (Barth et al, 1997;Terada and Hirokawa, 2000;Kneussel 2005;Marques 2005). Not surprisingly, therefore, disrupted neuronal microtubule dynamics has been suggested to be the underlying dysfunction of several human neurological diseases, including Fragile X Syndrome (FXS) and Hereditary Spastic Paraplegia (HSP) (Zhang et al, 2001;Huot et al, 2001;McDermott et al, 2003;Lu et al, 2004;Sherwood et al, 2004;Trotta et al, 2004;Zhang and Broadie, 2005;Orso et al, 2005). To study these disease states, we have developed FXS and HSP models in the Drosophila genetic system (Zhang et al, 2001;Trotta et al, 2004;Zhang and Broadie, 2005).…”

“…Not surprisingly, therefore, disrupted neuronal microtubule dynamics has been suggested to be the underlying dysfunction of several human neurological diseases, including Fragile X Syndrome (FXS) and Hereditary Spastic Paraplegia (HSP) (Zhang et al, 2001;Huot et al, 2001;McDermott et al, 2003;Lu et al, 2004;Sherwood et al, 2004;Trotta et al, 2004;Zhang and Broadie, 2005;Orso et al, 2005). To study these disease states, we have developed FXS and HSP models in the Drosophila genetic system (Zhang et al, 2001;Trotta et al, 2004;Zhang and Broadie, 2005). However, our studies, like all others (Huot et al, 2001;McDermott et al, 2003;Lu et al, 2004;Sherwood et al, 2004;Orso et al, 2005), have been hampered by the available, very indirect assays of microtubule states in neuronal synapses.…”

We Hold These Truths to be Self-evident, that All Flies and Men Are Created Equal: Recent Progress on Human Disease Models

“…Previous work has demonstrated that null mutations in the Drosophila spastin homolog recapitulate the motor defects associated with AD-HSP along with defects in synaptic structure and function. [25][26][27] Work presented at the conference by the Sherwood lab (Duke University, Durham, NC) focused on understanding Spas function through several genetic approaches in the fly. First they demonstrated that both wildtype fly and human Spas proteins rescue the null drosophila phenotypes showing the evolutionary conservation of protein function and further indicating the usefulness of this Drosophila model.…”