HD Lighthouse Contributing Editor's Comment: While therapeutic research -- drug discovery and development -- has thankfully increased in the last couple of years thanks to the High Q foundation and CHDI, basic research into Huntington's Disease pathology continues. When researchers identify a new target for drug development as the authors of the study below have done, it's exciting news for the HD community.

In a carefully done study involving human brain tissue and two mouse models of Huntington's Disease, Dr. Steven Hersch and colleagues found that excess copper in the brain contributes to HD pathology. This is a new finding, but as the authors point out, it's one that fits in with existing knowledge about the disease pathology.

Up until this point, more emphasis has been placed on excess iron as an HD pathology. However, tissue from the brains of people who died with HD show that copper is also elevated compared to controls.

Is this an early or later event? The R6/2 mouse shows an early elevation in both iron and copper. However, this mouse model gets sick very quickly and best models Juvenile Huntington's Disease or late stage HD. The knock in mouse more closely models the course of adult Huntington's Disease and in this mouse, iron is elevated early but copper elevation occurs later.

Why does the increase in copper occur? This isn't clear as yet but the excess copper is clearly pathological, not protective.

The HD protein and fragments interact directly with copper and reduce it from copper II to I. But there is still more copper to be found which is available to interact with the mutated huntingtin's protein and other proteins in a toxic way. Copper appears to promote aggregates which other recent research has shown to be centers of reactive oxidative species that damage components of cells through oxidative stress. And it is also possible that copper causes some early structural changes to the HD protein which render it more toxic.

How else does the excess copper cause damage? One way is by reducing the activity of Lactate dehydrogenase (LDH) which is important for energy metabolism. Copper doesn't reduce the amount of LDH but rather causes it to becomes less active. This is enough, in and of itself, to cause neurodegeneration in the striatum.

The researchers also found that the amyloid precursor proteins (which play a role in Alzheimer's) and ATPase (which play a role in Wilson's disease) are all reduced. These proteins act as copper exporters which means that the copper isn't getting to where it needs to go in the brain.

The authors point out that there are probably other things going on as well. For example, 3-hydroxykynurenine is elevated in HD and it interacts with copper to generate hydrogen peroxide. In the presence of hydrogen peroxide, copper can damage DNA by oxidizing it and we already have evidence suggesting that DNA oxidation is a marker for the disease. (see HDL: More evidence for creatine )

The role of copper in HD looks to me to be another important piece of the HD puzzle, one with implications for therapy. There are two copper chelators which might have therapeutic potential. One is clioquinol (or an analog) and the other is epigallocatechin-gallate, a flavinoid in green tea which also acts as an iron chelator.. Both have been covered on the Lighthouse and we'll continue to follow the research with both.

Hersch's article is open access and can be read here: [click here for article]

For a discussion of metal based neurodegeneration by Lighthouse contributor Mac Casale, Ph.D. see HDL: A Review of the Book Metal-Based Neurodegeneration From Molecular Mechanisms to Therapeutic Strategies

-- Marsha L. Miller, Ph.D.
Posted to the HDL: 02 Apr 2007

Jonathan H. Fox, Jibrin A. Kama, Gregory Lieberman, Raman Chopra, Kate Dorsey, Vanita Chopra, Irene Volitakis, Robert A. Cherny, Ashley I. Bush, Steven Hersch

Huntington's disease (HD) is caused by a dominant polyglutamine expansion within the N-terminus of huntingtin protein and results in oxidative stress, energetic insufficiency and striatal degeneration. Copper and iron are increased in the striata of HD patients, but the role of these metals in HD pathogenesis is unknown. We found, using inductively-coupled-plasma mass spectroscopy, that elevations of copper and iron found in human HD brain are reiterated in the brains of affected HD transgenic mice. Increased brain copper correlated with decreased levels of the copper export protein, amyloid precursor protein. We hypothesized that increased amounts of copper bound to low affinity sites could contribute to pro-oxidant activities and neurodegeneration. We focused on two proteins: huntingtin, because of its centrality to HD, and lactate dehydrogenase (LDH), because of its documented sensitivity to copper, necessity for normoxic brain energy metabolism and evidence for altered lactate metabolism in HD brain. The first 171 amino acids of wild-type huntingtin, and its glutamine expanded mutant form, interacted with copper, but not iron. N171 reduced Cu(2+)in vitro in a 1ratio1 copperratioprotein stoichiometry indicating that this fragment is very redox active. Further, copper promoted and metal chelation inhibited aggregation of cell-free huntingtin. We found decreased LDH activity, but not protein, and increased lactate levels in HD transgenic mouse brain. The LDH inhibitor oxamate resulted in neurodegeneration when delivered intra-striatially to healthy mice, indicating that LDH inhibition is relevant to neurodegeneration in HD. Our findings support a role of pro-oxidant copper-protein interactions in HD progression and offer a novel target for pharmacotherapeutics. # # #

Source: PLoS ONE 2(3): e334. doi:10.1371/journal.pone.0000334

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