Working with a new fruitfly model of HD, Baylor College of Medicine researchers have come up with some new insights about HD pathology.

Much of the focus of HD research has been on dysfunctions inside the cell - impaired cellular metabolism, accumulation of the huntingtin protein inside the nucleus, and interference with normal gene transcription. In the new fruit fly model, increased neurotransmission occurred before problems developed inside the cell.

Neurons are connected to each other by synapses and communicate through chemical signals called neurotransmitters. The Baylor researchers found that the release of neurotransmitters was actually more efficient than it is supposed to be.

They also identified genes which could ameliorate this problem. Inducing a partial loss of function in genes regulating synaptic function reversed the disease. Mutations in genes controlling calcium channel regulation also reduced the elevated transmission and reversed the pathology. Calcium channels trigger neurotransmission by controlling the influx of calcium into the neuron

By manipulating these genes, the researchers were able to suppress the impaired motor performance and neurodegeneration seen in the fruit fly model, showing that increased neurotransmission is an early and significant pathology.

Using different models of the disease

Fruitfly or drosophilia models of HD are used because results can be achieved faster than in mouse models of the disease. The insights gained are then explored further in mouse model studies.

In analyzing the results of any animal model study of HD, it is important to consider which model was used. There are different types of mouse models and each model reproduces human HD pathology somewhat differently. The earliest models, and the ones still used most often in research (the R6/1 and R6/2 mice), are those in which a segment of human CAG repeats have been added to the mouse's own huntingtin's gene. These models express a transgenic (meaning the gene is from another species) and truncated (not the full gene) version of the protein.

Other models include ones in which the entire human HD gene have been inserted (transgenic, full length) and ones in which extra mouse CAG repeats have been added to the mouse's own huntingtin's protein gene (knock-in models).

The mice in the truncated, transgenic models get sick very quickly, the disease is more severe, and nuclear protein aggregates form early. In contrast, the transgenic, full length and knock in models develop the disease later, nuclear aggregation occurs later, and the specific pattern of neurodegeneration reproduces that which is seen in human HD.

A landmark research study with knockin mice was done by Michael Hayden and colleagues. Their research supports the toxic fragment hypothesis, the idea that caspases cut the HD protein into toxic fragments which enter the nucleus and cause dysfunction and cell death. HD mice which are also genetically manipulated to be resistant to caspase six do not develop HD nor do the ‘short stop' mice where the protein fragments in a different place so that the fragments are not toxic. These insights could not have been obtained from the truncated mouse models.

Fruit fly or drosophilia models of HD were developed so that results can be achieved faster than in mouse models of the disease. The findings can then be explored further in mouse model studies. Before the BCM researchers developed the new model, truncated fruit fly models were used. Dr. Botas and colleagues developed a transgenic fruit fly model in which the entire human HD protein is expressed, hoping to find additional insights into the Huntington's disease process.

As with the mice, the disease progresses differently in the two fruit fly models. In the full length fly model, progressive neurodegeneration, impaired motor performance, and decreased survival time occurred. Aggregates were not found in the axons or the nucleus as with the truncated model, perhaps because these processes take time when the protein isn't already fragmented and the life span of the fruit fly is so short. By using a full-length protein model, the BCM researchers were able to identify a new and early pathology, increased neurotransmission, which deserves further investigation.

Why these findings are important

The HD protein produces many alterations in the brain and not all of them represent targets for treatment. Some alterations are pathological and do indeed lead to dysfunction and brain cell loss. However, other changes may be compensations for problems while still other alterations may not contribute to pathology at all. It is important to identify which alterations are significant pathologies to develop treatment strategies.

Until a treatment that targets the expression of the HD gene is developed and approved, a combination approach to therapy will likely be used. This study identifies what appears to be a significant, early pathology and suggests some additional drug targets for the research pipeline.

The authors wrote, "The genetic data showing suppression of the synaptic transmission and neurodegenerative phenotypes further define specific therapeutic targets and support the idea that CA 2+ channel antagonists, and perhaps other inhibitors of neurotransmission, offer an attractive therapeutic option due to their specificity and wide usage."

It seems worthwhile for a calcium channel antagonist to be investigated in a mouse model of the disease. A new study reports that individuals taking these drugs on a long term basis (for other medical reasons) reduced their risk of developing Parkinson's Disease by 23 percent, suggesting that they may be neuroprotective.

References

Becker C, Meier C, "Use of antihypertensives and the risk of Parkinson disease." Neurology 2008 Feb 6 [Epub ahead of print]

Hayden M, et al., "Cleavage at the Caspase-6 Site Is Required for Neuronal Dysfunction and Degeneration Due to Mutant Huntingtin." Cell, Vol 125, 1179-1191, 15 June 2006

E.J. Slow, et al, "Absence of behavioral abnormalities and neurodegeneration in vivo despite widespread neuronal huntingtin inclusions." Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, 11402-7, 9 Aug 2005.