The physiological and pathological functions of the hereditary spastic paraplegia protein spartin.
Lead Research Organisation:
University of Cambridge
Department Name: Cambridge Institute for Medical Research
Abstract
The hereditary spastic paraplegias (HSPs) are a group of neurodegenerative genetic disorders affecting the axons of motor neurons, and causing affected people to develop a progressive lower limb spasticity and weakness. There may be associated neurological and non-neurological symptoms. The pathology of the HSPs is primarily confined to the axons, with axonal degeneration, leaving an intact cell body. Therefore studying these diseases at a cellular level is essential in determining the necessary cellular pathways required for axonal health. Whilst these insights will be important for the HSPs, it is also likely they will have a wider application and be relevant to other neurodegenerative conditions affecting axons, such as motor neuron disease and multiple sclerosis.
The main aim of this project is to understand the functions of the protein spartin, as loss of spartin causes the HSP Troyer syndrome. A further aim is to determine how absent spartin leads to axonal degeneration. This project will also provide insight into whether there are common mechanisms underlying the pathology of the HSPs in general. A greater understanding of these processes may then enable us to consider new treatments for these and related diseases.
The main aim of this project is to understand the functions of the protein spartin, as loss of spartin causes the HSP Troyer syndrome. A further aim is to determine how absent spartin leads to axonal degeneration. This project will also provide insight into whether there are common mechanisms underlying the pathology of the HSPs in general. A greater understanding of these processes may then enable us to consider new treatments for these and related diseases.
Technical Summary
This project is aimed at understanding the normal and pathological functions of spartin, loss of which causes hereditary spastic paraplegia (HSP). HSPs are genetic conditions in which long axons in the spinal cord show dying-back axonopathy, and so they are excellent models to understand axonal maintenance and degeneration. .
Spartin is one of a group of endosomal HSP proteins. Abnormal endocytic function could cause HSP by dysregulating receptors controlling signaling pathways important for axons. We have shown that altered bone morphogenic protein (BMP) signaling is the cause of axonal abnormalities in Drosophila models of NIPA1 (an endosomal HSP protein) -HSP, and our preliminary data suggest that spartin regulates BMP signaling. I will confirm this, examine whether the mechanism is altered trafficking of BMP receptors, then examine whether the abnormal BMP signaling affects axonal growth pathways.
We have also found that spartin interacts with AIP4, a protein implicated in the endosomal trafficking of the cytokine receptor CXCR4. I will examine whether spartin is necessary for normal trafficking of this receptor. We have identified interactions between spartin and two proteins that may be novel endosomal accessory proteins. I will confirm these interactions and examine their mechanistic relevance to BMP and CXCR4 membrane traffic.
Spartin is one of a group of endosomal HSP proteins. Abnormal endocytic function could cause HSP by dysregulating receptors controlling signaling pathways important for axons. We have shown that altered bone morphogenic protein (BMP) signaling is the cause of axonal abnormalities in Drosophila models of NIPA1 (an endosomal HSP protein) -HSP, and our preliminary data suggest that spartin regulates BMP signaling. I will confirm this, examine whether the mechanism is altered trafficking of BMP receptors, then examine whether the abnormal BMP signaling affects axonal growth pathways.
We have also found that spartin interacts with AIP4, a protein implicated in the endosomal trafficking of the cytokine receptor CXCR4. I will examine whether spartin is necessary for normal trafficking of this receptor. We have identified interactions between spartin and two proteins that may be novel endosomal accessory proteins. I will confirm these interactions and examine their mechanistic relevance to BMP and CXCR4 membrane traffic.