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Investigating modifiers transcripts in models of motor neuron disease

About This PhD Project

Project Description

The term ‘motor neuron disease’ refers to a group of disorders in which motor neurons are the primary target. The search for therapeutic agents to treat motor neuron disease often focuses on one subtype with a specific cause. However, when considering potential treatments for motor neuron diseases, it would therefore be of great value to identify druggable targets which could cross disease subtype and benefit multiple motor neuron diseases, regardless of the cause.

This project is based upon the observation that in patients and animal models, distinct motor neuron populations are differentially vulnerable. We aim to use this scenario to identify novel neuroprotective transcripts and mechanisms. We have already performed an RNAseq screen on motor neurons which are differentially vulnerable in mouse models of the childhood MND Spinal Muscular Atrophy (SMA; (Murray et al., 2015)). We next re-analysed 3 published microarray screens based upon motor neurons which were differentially vulnerable in other MNDs, including ALS, and identified commonalities between these screens and our data set (Brockington et al., 2013; Hedlund et al., 2010; Kaplan et al., 2014). So far, we have used viral vectors (scAAV9) to over express two of our most exciting candidates in a mouse model of SMA and both conferred an extension in life span and protection of the motor neuron. This work demonstrates that the transcripts identified can modify motor neuron pathology in SMA. We now aim to investigate whether these transcripts can be neuroprotective to motor neurons against a range of pathological mutations.

In this project, we aim to use cellular and animal models of motor neuron disease to investigate whether these transcripts can confer any neuroprotective effect. Transcript levels will be altered in model systems (e.g. cellular or mouse models) and we will investigate any neuroprotective effects using model appropriate assays (e.g. viability, neurite length, motor neuron pathology). The ultimate goal of this work is to identify transcripts which can modify motor neuron pathology caused by a range of genetic insults.

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