Degeneration & Disease

Building on strengths in basic neurobiology (and in collaboration with the MRC Toxicology Unit), there is a growing emphasis on translational research into clinically-relevant neurological  disorders.

The mechanisms underlying neurodegenerative diseases such as Huntington’s, Parkinson’s, Alzheimer’s and prion diseases are examined at different biological levels, ranging from the use of yeast screens  to identify candidate disease modifiers, to the analysis of disease processes and behavioural effects in animals. An area of particular expertise is transcriptomic profiling, which extends to studies in human subjects. In an orthogonal approach, electrophysiology and molecular sensors monitor synaptic activity in real time, allowing investigation of the early stage disease at individual synapses.

Research into brain damage caused by loss of blood supply (ischemia) includes mechanisms relevant to the developing as well as the mature adult brain. One line of our stroke research investigates the damage caused by ischemia-induced release of neuro-transmitters and the potential for agents such as steroids to reduce this damage. Another recent finding regarding ischemic injury during development implicates damage to the glial cells (oligodendrocytes) that form the surrounding myelin of axons. This raises the possibility that these cells play a key role in intra-uterine brain damage, a leading cause of cerebral palsy. Moreover, this finding may yield a new prospective approach to prevent such events.

Research Highlights

• Inhibition of an enzyme involved in tryptophan metabolism prevents excitotoxicity-related neurodegeneration, making it a potential therapeutic target in HD and other neurodegenerative diseases.  Campesan et al., Current Biology 21, 961, 2011; Zwilling et al., Cell 145, 863 2011.
• Prion-induced neurodegeneration results from an overall blockade of protein synthesis mediated by hyperphosphorylation of elF-2alpha. Moreno et al., Nature 485, 507, 2012.
• A novel gene expression analysis method enables simultaneous monitoring of multiple human brain cell populations in a single assay. Kuhn et al Nature Methods 8, 945 2011.
• Progesterone treatment prevents aged female subjects against ischemic brain damage Gibson et al. Brain 134, 2125 2011.
• Glutamate receptor-mediated ischemic injury of premyelinated central axons. Alix & Fern, Ann Neurol. 66, 682- 93. 2009.