HD is one of a growing number of human diseases known to be caused by such ‘genetic stutters’
Over the past two decades, our research team has played a key role in understanding how the ‘genetic stutter’ causing Huntington’s disease (HD) leads to a cascade of pathological processes, at the levels of molecules, cells, brain circuits, behaviour, cognition and mood. HD is one of a growing number of human diseases known to be caused by such ‘genetic stutters’, which are called tandem repeat disorders (reviewed by Hannan, 2018, Nature Rev. Genet.). One of our major discoveries involved the first evidence that environmental stimulation (including increased cognitive stimulation and physical activity) can be beneficial (van Dellen et al., 2000, Nature). We then went on to show that increased exercise can have beneficial effects in delaying onset of Huntington’s disease in a preclinical model (Pang et al., 2006, Neuroscience). More recently, we provided evidence that chronic stress and increased stress hormone can accelerate onset of dementia in this HD model (Mo et al., 2014, Neurobiol. Dis.). One of our most recent discoveries is that the gut microbiome (the trillions of bacteria living in the gastrointestinal tract) is abnormal in this preclinical model of Huntington’s disease (Mo et al., 2018, Neurobiol. Dis.).
Our research team at the Florey Institute is trying to use this knowledge of pathology, in the brain and other areas of the body, to develop new treatments for Huntington’s disease. We have shown that our preclinical model of Huntington’s disease (which expresses the gene mutation present in patients) provides a very accurate model, including changes at the levels of molecules, cells, cognition and behaviour. We have discovered promising new candidate therapeutic approaches for HD (e.g. Wright et al., 2015, Transl. Psychiatry; Wright et al., 2016, Hum. Mol. Genet.) and we are working with clinical colleagues to translate these discoveries.
Our research has led to new insights into gene-environment interactions in various brain disorders, including Huntington’s disease, dementia, depression, schizophrenia and autism spectrum disorders. We explore how genes and environment combine via experience-dependent plasticity in the healthy and diseased brain, including HD. Ongoing research includes a preclinical model of HD investigated at behavioural, cellular and molecular levels so as to identify pathogenic mechanisms and novel therapeutic targets for drug development.
Professor Anthony Hannan, NHMRC Principal Research Fellow and Laboratory Head, Florey Institute of Neuroscience and Mental Health
Phone: +61 3 9035 6638