Mechanisms of copper ion mediated Huntington's disease progression
| Autor: | Raman Chopra, Vanita Chopra, Jibrin A. Kama, Robert A. Cherny, Jonathan H. Fox, Irene Volitakis, Ashley I. Bush, Kate Dorsey, Steven M. Hersch, Gregory Lieberman |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
medicine.medical_specialty
Huntingtin Iron lcsh:Medicine Nerve Tissue Proteins medicine.disease_cause Chromatography Affinity Superoxide dismutase 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Huntington's disease Internal medicine Lactate dehydrogenase medicine Amyloid precursor protein Huntingtin Protein Animals Humans lcsh:Science 030304 developmental biology Cerebral Cortex 0303 health sciences Multidisciplinary biology Superoxide Dismutase Neurodegeneration lcsh:R Brain Nuclear Proteins medicine.disease 3. Good health Oxidative Stress Endocrinology Huntington Disease Biochemistry chemistry biology.protein Disease Progression Lactates Mice Inbred CBA lcsh:Q 030217 neurology & neurosurgery Oxidative stress Copper Research Article Neuroscience |
| Zdroj: | PLoS ONE PLoS ONE, Vol 2, Iss 3, p e334 (2007) |
| ISSN: | 1932-6203 |
| Popis: | 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 1:1 copper:protein 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. |
| Databáze: | OpenAIRE |
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