SSA: Analysis of Gene Interactions in Neurodegeneration

The striatum is a key component of the basal ganglia in the forebrain. One of its important roles is in the control of voluntary movement. Its principle neuronal type, the medium spiny neuron (MSN) degenerates in the progressive neurodegenerative condition Huntington's Disease (HD). The causal mutation is expansion of the "CAG repeat" of the Huntingtin (Htt) gene. Importantly, HD is established as a paradigm for understanding neurodegeneration more generally. Understanding the molecular mechanism that produce MSNs in normal brain development and the mechanisms by which mutant Htt (mHtt) leads to MSN degeneration are important questions in neuroscience. In the longer term, they are both critical to producing new treatments for HD (no disease modifying treatments are currently available). An established approach for progress is to use model organisms as an in vivo system for the required mechanistic analysis. The mouse is a favoured model for MSN research. We use it to investigate the cell differentiation pathway that produces MSNs during brain development and have identified two transcription factor-encoding genes, Mef2C and FoxP1, required for normal striatal MSN development. Intriguingly, both Mef2D (closely related to Mef2C) and FoxP1 are reported to suppress mHtt-induced neurodegeneration in a Drosophila model. This implicates these transcription factors not only in the developmental pathways, but also in rescue of neurodegeneration.

To explore these novel findings, you will use diverse techniques from genetics and neurosciences. In vivo genetic analysis in the classic model organism, Drosophila, has many advantages with its sophisticated range of techniques that give rapid insight. You will use Drosophila to complement the mouse by efficiently testing hypotheses. Only analyses most likely to be informative will be brought to the mouse, which has closer links to human biology, but where experiments take much longer. You will use the Drosophila eye as an in vivo "test tube" to analyse mammalian gene function in neurodegeneration. It provides a simple readout of this phenomenon. You will use genetic tools to drive expression of mHtt in the eye to induce neurodegeneration and then test genetic modifiers of this process. Initial results will guide subsequent mechanistic analysis. Your complementary experiments will use a mouse model that expresses mHtt and produces a mild HD-like phenotype. You will assess this with a behavioural assay and immuno-histochemistry for neuronal inclusions and MSN markers, and then test effects of up- or down-regulation of candidate genes on this neurodegeneration phenotype.