HD Lighthouse Contributing Editor's Comment:

Here is yet another contribution to our understanding of early pathology in Huntington's Disease.

We know that the CAG count influences the amount of cellular energy (the ATP/ADP ratio). The lower the CAG count, the greater the amount of cellular energy available. The higher the CAG count, the less the amount of cellular energy. This is true across the whole spectrum of CAG counts, from the normal range to the HD range.

It has been thought that the HD protein might directly affect the mitochrondia, the cell's energy factories. This was a reasonable hypothesis and in fact a neurotoxin which affects the mitochondia produces symptoms similar to HD. An early model of Huntington's Disease involved administering a neurotoxin called 3-nitropropionic acid or 3-NP. 3-NP inhibits mitochondria, destroys cells in the striatum and causes HD like symptoms.

To see if HD is indeed like 3-NP, the researchers first looked more closely at what was going on with energy problems and then examined gene expression in normal striatal cells, cells with the HD protein, and normal cells which had been treated with 3-NP.

There were some similarities. Both the striatal cells with the HD protein and the 3-NP treated cells had decreased mitochondrial respiration and membrane potential. However, reactive oxygen species increased in the 3-NP cells but decreased in the HD cells. While succinate dehydrogenase activity decreased in the 3-NP cells, this respiratory chain component was unchanged in the HD cells.

They then examined gene expression and found that the 3-NP treated cells failed to express mitochondrial genes while the HD striatal cells continued to express those genes.

The researchers concluded that the pathways by which cellular energy is lost are clearly different for 3-NP and the expanded polyglutamine tract of the HD gene.

So what is causing the reduction in cellular energy if it is not direct damage to the mitochondria? They analyzed transcription factors and found that it is not problems with the NRSF/REST target genes. This was a good hypothesis given the research coming from Dr. Cattaneo's lab but it turns out that reduced cellular energy is a separate pathology. More work needs to be done, but some evidence points to redox sensing cell signaling. If it is, this opens up new therapeutic targets. The authors note that "the molecules and gene products that modify oxidation-sensitive signaling in metabolic disorders may become candidates for modifying huntingtin-regulated mitochondrial metabolism in HD." These same therapies are also of interest as treatments for cancer and various metabolic disorders. [note: Redox signaling is the concept that free radicals, reactive oxygen species (ROS), and other electronically-activated species act as messengers in biological systems.]

Why is this important for HD families? Although we are all eagerly awaiting more phase III clinical trials, basic research studies like this one are needed to help researchers to find targets for drug development and to prioritize trials. Boosting cellular energy promises to be a major therapeutic strategy and it's important to learn how to best do that.

Also important is that this research represents success in carrying out part of a strategic plan . Just as CHDI has a strategic plan to develop drugs for clinical testing, the basic researchers have a strategic plan for facilitating this process by targeting their research to answer key questions about the major pathologies in the brain that are caused by HD.

There were five teams set up. They are:

1. mitochondria and energy metabolism
2. folding, aggregation, and clearance of mutant huntingtin
3. huntingtin proteolysis and post translational modification
4. transcription
5. huntingtin function

Having discovered that the HD protein doesn't directly affect the mitochondria, the mitochondria team has now disbanded and the members are working on teams 3 and 5 to study how the mitochondria are being managed.

As HDlighthouse readers can see from the exciting new basic research studies being published this summer, the pieces of the puzzle keep coming together.

-- Marsha L. Miller, Ph.D.
Posted to the HDL: 26 Aug 2007

Unbiased Gene Expression Analysis Implicates the huntingtin Polyglutamine Tract in Extra-mitochondrial Energy Metabolism

Jong-Min Lee, Elena V Ivanova, Ihn Sik Seong, Tanya Cashorali, Isaac Kohane, James Gusella, Marcy MacDonald

The Huntington's disease (HD) CAG repeat, encoding a polymorphic glutamine tract in huntingtin, is inversely correlated with cellular energy level, with alleles over ∼37 repeats leading to the loss of striatal neurons. This early HD neuronal specificity can be modeled by respiratory chain inhibitor 3-nitropropionic acid (3-NP) and, like 3-NP, mutant huntingtin has been proposed to directly influence the mitochondrion, via interaction or decreased PGC-1α expression. We have tested this hypothesis by comparing the gene expression changes due to mutant huntingtin accurately expressed in STHdhQ111/Q111 cells with the changes produced by 3-NP treatment of wild-type striatal cells. In general, the HD mutation did not mimic 3-NP, although both produced a state of energy collapse that was mildly alleviated by the PGC-1α-coregulated nuclear respiratory factor 1 (Nrf-1). Moreover, unlike 3-NP, the HD CAG repeat did not significantly alter mitochondrial pathways in STHdhQ111/Q111 cells, despite decreased Ppargc1a expression. Instead, the HD mutation enriched for processes linked to huntingtin normal function and Nf-κB signaling. Thus, rather than a direct impact on the mitochondrion, the polyglutamine tract may modulate some aspect of huntingtin's activity in extra-mitochondrial energy metabolism. Elucidation of this HD CAG-dependent pathway would spur efforts to achieve energy-based therapeutics in HD. # # #

Source: PLoS Genet. 2007 August; 3(8): e135.

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