Gene therapy in a mouse model of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Amyotrophic Lateral Sclerosis (ALS, also known as motor neuron disease) and fronto-temporal dementia (FTD) are fatal neurodegenerative diseases for which no effective therapies currently exist. ALS causes muscular paralysis due to progressive motor neuron degeneration and FTD causes progressive changes to personality, behaviour and language. Despite a large number of underlying genetic defects 95% of ALS and tau-negative FTD patients share a common pathology at post-mortem revealing cytoplasmic inclusions containing TDP-43 protein (Neumann et al., 2006). TDP-43 is a DNA and RNA binding protein that plays a major role in regulating the transcription, editing, transport and translation of ~6,000 different RNA transcripts. We have shown that mutant and wild-type forms of TDP-43 protein can misfold, aggregate and become highly neurotoxic in a range of cellular and animal models (Sreedharan 2008; Scotter 2013 and Mitchell 2015). This project aims to explore the potential of gene therapies designed to remove TDP-43 aggregates and prevent neurodegeneration.

We have recently discovered that several members of a family of specialised chaperones, called heat shock proteins (HSPs), are able to refold and enhance the clearance of aggregated TDP-43 (Chen 2016). We showed that expression of Heat Shock Factor 1 (HSF1), the master transcription factor driving the chaperone response, is able to dramatically clear TDP-43 aggregates and rescue cultured cells. Interestingly the levels of HSF1 and HSPs are significantly reduced in the spinal cord tissues of both ALS patients and a TDP-43 transgenic mouse, suggesting the loss of this pathway is disease-critical (Chen et al., 2016).

The first potential gene therapy we plan to test in our TDP-43 transgenic mouse model of ALS and FTD is HSF1 to determine whether we can drive HSP-mediated rescue of TDP-43 aggregation and toxicity (Mitchell 2015). A dominantly active form of HSF1(+), will be delivered to mouse brain and spinal cord tissues by injection of the adeno-associated virus AAV in pre-symptomatic and symptomatic TDP-43 transgenic mice. The therapeutic effect of HSF1(+) will be evaluated in live animals by measuring motor phenotypes and cognitive tasks and survival. In brain and spinal cord tissues will measure the heat shock protein levels achieved following HSF1 expression and the clearance of aggregated TDP-43 from neural tissues. This study will provide principle foundation on the potential of HSF1 as gene therapy for ALS and other neurodegenerative diseases associated with protein aggregation. Other gene therapy targets and approaches will be explored during the project.

The student will join one of the world’s leading ALS and FTD laboratories in the newly built Wohl Institute where they will acquire cutting-edge expertise in many molecular biology and gene therapy techniques including the generation of viral vectors, microsurgery, behavioural phenotyping, western blotting and immunocytochemistry using state-of-the-art microscopy and image analysis.

Applicants should have (or be expected to obtain) a 2:1 or 1st class honours degree in a subject relevant to the proposed project. If applicants already possess (or expect to obtain) a research-based MSc degree, a merit or distinction level is required.