Huntington Disease

Publication Title: 
Proceedings of the National Academy of Sciences of the United States of America

In investigating the role of metal ions in the pathogenesis of Huntington's disease, we examined the effects of clioquinol, a metal-binding compound currently in clinical trials for Alzheimer's disease treatment, on mutant huntingtin-expressing cells. We found that PC12 cells expressing polyglutamine-expanded huntingtin exon 1 accumulated less mutant protein and showed decreased cell death when treated with clioquinol. This effect was polyglutamine-length-specific and did not alter mRNA levels or protein degradation rates.

Nguyen, Trent
Hamby, Aaron
Massa, Stephen M.
Publication Title: 
Aging Cell

Aging and age-related diseases can be viewed as the result of the lifelong accumulation of stress insults. The identification of mutant strains and genes that are responsive to stress and can alter longevity profiles provides new therapeutic targets for age-related diseases. Here we reported that a Drosophila strain with reduced expression of ribose-5-phosphate isomerase (rpi), EP2456, exhibits increased resistance to oxidative stress and enhanced lifespan. In addition, the strain also displays higher levels of NADPH.

Wang, Ching-Tzu
Chen, Yi-Chun
Wang, Yi-Yun
Huang, Ming-Hao
Yen, Tzu-Li
Li, Hsun
Liang, Cyong-Jhih
Sang, Tzu-Kang
Ciou, Shih-Ci
Yuh, Chiou-Hwa
Wang, Chao-Yung
Brummel, Theodore J.
Wang, Horng-Dar
Publication Title: 
Nature Chemical Biology

In polyglutamine (polyQ) diseases, only certain neurons die, despite widespread expression of the offending protein. PolyQ expansion may induce neurodegeneration by impairing proteostasis, but protein aggregation and toxicity tend to confound conventional measurements of protein stability. Here, we used optical pulse labeling to measure effects of polyQ expansions on the mean lifetime of a fragment of huntingtin, the protein that causes Huntington's disease, in living neurons.

Tsvetkov, Andrey S.
Arrasate, Montserrat
Barmada, Sami
Ando, D. Michael
Sharma, Punita
Shaby, Benjamin A.
Finkbeiner, Steven
Publication Title: 
Scientific American
Rose, M. R.
Publication Title: 
Free Radical Biology & Medicine

Oxidative stress is a prominent feature of Huntington's disease (HD) due to mitochondrial dysfunction and the ensuing overproduction of reactive oxygen species (ROS). This phenomenon ultimately contributes to cognitive and motor impairment, as well as brain pathology, especially in the striatum. Targeting the transcription of the endogenous antioxidant machinery could be a promising therapeutic approach. The NF-E2-related factor-2 (Nrf2)/antioxidant response element (ARE) signaling pathway is an important pathway involved in antioxidant and anti-inflammatory responses.

Stack, Cliona
Ho, Daniel
Wille, Elizabeth
Calingasan, Noel Y.
Williams, Charlotte
Liby, Karen
Sporn, Michael
Dumont, Magali
Beal, M. Flint
Publication Title: 
Neurobiology of Disease

Huntington's disease (HD) is a lethal, neurodegenerative disorder caused by expansion of the polyglutamine repeat in the Huntingtin gene (HTT), leading to mutant protein misfolding, aggregation, and neuronal death. Feeding a Drosophila HD model cystamine, or expressing a transgene encoding the anti-htt intracellular antibody (intrabody) C4-scFv in the nervous system, demonstrated therapeutic potential, but suppression of pathology was incomplete.

Bortvedt, S. F.
McLear, J. A.
Messer, A.
Ahern-Rindell, A. J.
Wolfgang, W. J.
Publication Title: 
Physiology & Behavior

Ketogenic diets are high in fat and low in carbohydrates, and have long been used as an anticonvulsant therapy for drug-intractable and pediatric epilepsy. Additionally, ketogenic diets have been shown to provide neuroprotective effects against acute and chronic brain injury, including beneficial effects in various rodent models of neurodegeneration. Huntington's disease is a progressive neurodegenerative disease characterized by neurological, behavioral and metabolic dysfunction, and ketogenic diets have been shown to increase energy molecules and mitochondrial function.

Ruskin, David N.
Ross, Jessica L.
Kawamura, Masahito
Ruiz, Tiffany L.
Geiger, Jonathan D.
Masino, Susan A.
Publication Title: 
Journal of Medical Genetics

Data from the US National Huntington's Disease Roster have been analysed in terms of the difference in age of onset (AO) between affected parents and affected offspring, that is, in terms of 'anticipation'. While mean AO in offspring of affected mothers did not differ greatly from AO in their mothers, the distribution of AO in the offspring of affected fathers falls into two groups, the larger group showing an AO only slightly younger than their affected fathers and a small group whose AO was, on average, 24 years younger than their affected fathers.

Ridley, R. M.
Frith, C. D.
Crow, T. J.
Conneally, P. M.
Publication Title: 
Clinical Genetics

A study of very early onset Huntington's disease (VEOHD) has shown that at least 38% of gene-carrying sibs also develop symptoms before the age of 10, thus improving the genetic risk for those sibs who remain healthy. The prevalence of VEOHD among sibs shows that mutation during spermatogenesis is most unlikely to account for these uncommon cases. The data suggest that two mechanisms contribute to VEOHD: modification by many genes (individually of small effect), and an epigenetic mechanism occurring when transmission is through a series of males.

Clarke, D. J.
Bundey, S.
Publication Title: 
Neurobiology of Disease

Huntington's disease (HD) is a devastating disorder that affects approximately 1 in 10,000 people and is accompanied by neuronal dysfunction and neurodegeneration. HD manifests as a progressive chorea, a decline in mental abilities accompanied by behavioural, emotional and psychiatric problems followed by, dementia, and ultimately, death. The molecular pathology of HD is complex but includes widespread transcriptional dysregulation.

Buckley, Noel J.
Johnson, Rory
Zuccato, Chiara
Bithell, Angela
Cattaneo, Elena


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