Three New Research Projects Under Way, Thanks to HSC Research Grants

The Huntington Society awarded three research grants through the NAVIGATOR Coalition program this spring, totaling $75,000. These grants will fund projects to increase our knowledge of CAG repeats, the huntingtin protein, and memory problems in people with HD.

NAVIGATOR is the Society's main research program, through which the majority of research funds are awarded. The aim of the NAVIGATOR Coalition program is to fund the most promising research in HD in Canada in a variety of research areas. Applications received through the program are peer reviewed by members of the Society's Research Council, with some support from external reviewers. Applications are reviewed to determine their scientific excellence, as well as their contribution to the knowledge of Huntington disease.

Requests for applications were distributed widely to research institutions across Canada, and three proposals were recommended by our Research Council to receive funding.

Dr. Susan Andrew, University of Alberta
The role of FEN1 in stability of the CAG repeat underlying Huntington disease

Huntington disease (HD) is caused by more CAG repeats than normal in someone's DNA: something called trinucleotide expansion. Dr. Susan Andrew is trying to figure out the genetic mechanisms that cause this expansion.

Andrew is focusing on an enzyme called flap endonuclease or FEN1. When new DNA is being formed, FEN1 comes along and trims the extra branches of DNA that get created. It's an important job, because if these flaps of DNA aren't trimmed, they could mistakenly end up in new copies of the DNA ... perhaps as trinucleotide repeats. For example, yeasts without FEN1 have a lot more DNA expansion than other yeasts, and trinucleotide repeats are more common. In mice, cells without FEN1 die.

Andrew believes that FEN1 may not be working properly in people with HD. To test this idea, she will examine mice with only half the normal number of FEN1 genes and see if there is any link to an expanded number of CAG repeats. She will breed these mice with mice that have the HD gene. Then she'll compare mice with HD and normal number of FEN1 genes to mice with HD and half the FEN1 genes, looking for any CAG repeat expansion in brain cells, liver cells, sperm cells and egg cells. Finally, she'll keep breeding these mice to see if any CAG repeat expansion shows up in the next generations.

Ultimately, the results of this research will help to us understand what causes too many trinucleotide repeats in human neurodegenerative disorders, and suggest ways that we could prevent or treat them.

Dr. Ray Truant, McMaster University
Co-visualization of huntingtin and huntingtin-associated proteins in living striatal cells

We know that the HD gene produces a mutant form of the huntingtin protein. We know that the abnormal protein gets cut into two fragments, and some of those fragments form protein balls in the cell nucleus. We suspect that this process is somehow involved in killing certain brain cells, but we don't know exactly how that happens. What if we could actually watch mutant huntingtin in a live brain cell and see what it does? Ray Truant's research does just that.

Truant has been able to tag huntingtin with glowing bits of protein from certain jellyfish and watch it in a living brain cell using a sophisticated computer-controlled microscope. Using this approach, he has been able to watch mutant huntingtin protein form, protein balls appear, and brain cells die - all within 24 hours.

What Truant wants to do now is understand how and why mutant huntingtin fragments accumulate in the nucleus of certain brain cells, and why this leads to cell death in only some brain cells. He plans to look at how huntingtin moves into the nucleus, using these fluorescent tags. He also plans to tag mitochondria, the energy centres of the cell, and watch how they behave during this process, since we know HD affects the function of the mitochondria.

This work could lead to new targets for drugs that might help the function of normal huntingtin or prevent the function of mutant huntingtin.

Dr. Martin Lepage, McGill University
Memory retrieval and fronto-striatal dysfunction in Huntingon disease: An fMRI study

One of the many symptoms of HD is memory loss. People with HD have trouble accessing memories from their brain, and this can hurt job performance and make social interaction difficult. We know the memories are still there, because people with HD do fine on recognition tests - they just can't retrieve those memories when they need them.

Earlier research has shown that the prefrontal and subcortical regions of the brain are responsible for memory retrieval. Martin Lepage hopes to discover whether these are the areas that aren't working properly when people with HD try to access memories.

Lepage plans to compare 15 healthy people and 15 people with HD. He will use a powerful MRI machine to watch which areas of the brain light up (or don't light up) while his subjects do recognition tests and memory retrieval tests. By pinpointing the precise structures in the brain that are responsible for memory failures in people with HD, Lepage will increase our understanding of the cognitive symptoms of HD and provide researchers with a sensitive measure of the severity of the disease. As new drugs are developed to protect the brain from HD, researchers can use these measures to test how well the drugs work.