Florey researchers reveal Huntington's secrets

Neuroscience researchers have found evidence that environmental factors play a major role in accelerating or delaying the onset and progression of the lethal brain disorder Huntington's disease in a mouse model.

Dr Tony Hannan's team at the Howard Florey Institute of Experimental Medicine in Melbourne exposed transgenic mice, developed by Dr Jill Bates' group at Oxford University in the UK, to an enriched sensory environment, and showed that the cognitive stimulation significantly delayed the appearance of symptoms, and reduced their severity.

The mice carry a knock-in copy of variant of the human huntingtin gene that would normally result in them developing early symptoms of Huntington's disease in early adulthood.

The symptoms of Huntington's disease include chorea (jerky movement of the arms and legs resulting from loss of motor coordination), difficulties with speech, swallowing, concentration and memory, as well as psychiatric symptoms such as depression.

Huntington's disease is one of a class of unusual inherited disorders that exhibit a phenomenon called anticipation -- the parents may exhibit no symptoms, but 50 per cent of their children develop the disease, and the age of onset decreases, while the severity of the disease increases, with each subsequent generation.

The huntingtin gene's first protein coding sequence, or exon, contains a series of trincleotide CAG (glutamine) repeats that 'expands' spontaneously between generations.

If the expansion exceeds a critical threshold of 35 repeats, it disrupts the normal function of the huntingtin protein. The resulting, near-global neurotoxic effects kill the neurons of the cerebral cortex and striatum, with catastrophic effects on memory, higher cognitive functions, and motor coordination.

Hannan said Bates' team has produced transgenic mice with a knock-in 115-trinucleotide repeat of the human huntingtin gene, as well as a mouse carrying a knock-in copy of the critical first exon of the human gene within its own huntingtin gene.

All humans carry the gene, but if the trinucleotide repeat number is between 5 and 35, there is no effect -- beyond this figure, the gene becomes unstable, and expands spontaneously. The repeat number correlates strongly with the age of onset -- at 200 repeats, children as young as 1 or 2 may begin to exhibit symptoms, and die in early childhood.

Hannan said the disorder also seems to develop earlier and becomes more rapidly severe if the defective gene is paternally inherited. Individuals with 35 to 39 repeats do no always develop the disorder, and those who do tend to develop the disease very late in life. He said that in this threshold zone, an intellectually stimulating environment might make the difference between developing the disorder, and living a normal, full life span.

The transgenic mice in the Florey experiments lived in normal mouse cages with standard bedding, food and water, but were exposed to unusual scents, objects designed to stimulate their memory, and extra physical activity.

The Florey and Oxford researchers have found molecular evidence for the benefits of a stimulating environment, in the form of higher levels of key neurotransmitters in tissues from the neocortex and other regions in mice living in an enriched environment, relative to controls.

They believe the link between environmental changes and neural plasticity -- the formation of new nerve connections -- provides an insight into the way gene-environment interactions may delay the onset and progression of Huntington's disease and other neurodegenerative disorders.

Alzheimer's link

Research has also shown that confinement to an environment that provides insufficient intellectual stimulation -- like a nursing home -- may hasten the neurodegenerative process in Alzheimer's disease.

Even though a diagnostic test has been available for more than a decade, many members of families with a history of Huntington's disease decline to take it, because of the potential psychological impact of an adverse result.

Hannan said it was quite possible that depression -- a common problem in family members who test positive for the pathological form of the gene -- could actually hasten the onset of Huntington's disease by causing people to withdraw socially, and become less responsive to other forms of intellectual stimulation from their environment.

The Florey researchers are working to identify potential molecular targets for new drugs that may slow the onset of the disease.

Hannan said the drugs could be developed to slow early changes in gene transcription and synaptic function in affected regions of the brain.