Investigating a novel phenotype of lysosomal dysfunction in spartin-HSP

Rachel Allison, Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research

Project Summary

A defining feature of nerve cells (neurons) is that they rapidly communicate over long distances.  This communication is provided by direct connections between neurons in cable-like structures called axons.  However, sometimes axons become unhealthy and degenenerate. This is a key event in the progression of a number of major neurodegenerative diseases, including the hereditary spastic paraplegias (HSPs).  A fundamental question in neuroscience is understanding the molecular mechanisms required to maintain healthy axons.  I aim to help answer this question and do so by studying HSP. 
The HSPs are a group of inherited neurological disorders, the main pathological feature of which is the degeneration of the longest axons in the spinal cord. As HSPs are genetic conditions, identifying the responsible genes enables identification of specific proteins required for axon health.  Previously my work has focussed on the cell biology of spastin (SPG4), mutations in which are the most common cause of HSP.  This work has shown that spastin is essential for the normal cellular functions of the lysosome (the cellular degradation and recycling centre).  This is emerging as a common theme in HSP, and many known HSP proteins have a role at the lysosome.
In this project, I will focus on defining the cell biology of spartin (SPG20) in lysosomal function.  Gene mutations causing loss of spartin are responsible for Troyer syndrome, a type of HSP.  I will investigate the mechanisms by which spartin controls lysosome function and the effects of spartin loss on these processes.  This project will help confirm the importance of lysosome function as a key regulatory point in HSP and further our understanding of the cellular basis of the disease.  It has the potential to assist in the development of therapeutic strategies, via identification of drug targets that may be globally relevant or unique to a specific class of HSP.