The term motor neuron disease refers to a group of disorders in which motor neurons are lost. These disorders are generally severely disabling and frequently fatal within months to years of diagnosis.
Recent work has revealed that over expression of a gene known as alpha-synuclein is protective in mouse models of motor neuron disease. There are two emerging themes which could account for the neuro-protective effects of alpha-synuclein on motor neurons. Firstly, alpha-synuclein has been shown to protect neurons against a variety of stress inducing toxic insults, as this is thought to happen by it’s ability to down regulated the JNK cell stress pathway which promotes apoptosis. Alternatively, alpha-synuclein over expression has been shown to rescue defects in the SNARE complex and increase vesicle release at the NMJ. It is possible that defects in vesicle release and recycling which have been reported at the NMJ in mouse models of motor neuron disease can be rescued by an over expression of alpha-synuclein.
In this project, we aim to understand how over expression of alpha-synuclein exerts it’s beneficial effects. We will first use a combination of mouse and cellular model systems to investigate whether there are defects in synaptic vesicle release or recycling, and investigate whether increasing the levels of alpha-synuclein can impact upon any of these potential defects. Subsequently we will use mouse models of SMA to investigate whether there is an increase in the JNK cell stress pathway, and determine whether the activity of this pathway is reduced when alpha-synuclein levels are increased.
Dr Lyndsay Murray
Dr Karen Smillie