Huntington's Disease Research Today is a free monthly online journal that collates and summarizes the latest research about Huntington's Disease, including details on genetics, causes, symptoms, treatment.

Huntingtin-associated protein-1 is a modifier of the age-at-onset of Huntington's disease.

Metzger S, Rong J, Nguyen HP, Cape A, Tomiuk J, Soehn AS, Propping P, Freudenberg-Hua Y, Freudenberg J, Tong L, Li SH, Li XJ, Riess O

Department of Medical Genetics, University of Tuebingen, 72076 Tuebingen, Germany.

A polyglutamine repeat expansion of more than 36 units in a protein called huntingtin (htt) is the only known cause of Huntington's disease (HD). The expanded repeat length is inversely correlated with the age-at-onset (AAO), however, the onset age among HD patients with CAG repeats below 60 units varies considerably. In addition to environmental factors, genetic factors different from the expanded CAG repeat length can modify the AAO of HD. We hypothezised that htt interacting proteins might contribute to this variation in the AAO and investigated human htt-associated protein-1 (HAP1) using genetic and functional assays. We identified six polymorphisms in the HAP1 gene including one that substitutes methionine (M441) for threonine (T441) at amino acid 441. Analyzing 980 European HD patients, we found that patients homozygous for the M441 genotype show an 8-year delay in the AAO. Functional assays demonstrated that human M441-HAP1 interacts with mutant htt more tightly than does human T441-HAP1, reduces soluble htt degraded products and protects against htt-mediated toxicity. We thus provide genetic and functional evidence that the M441-HAP1 polymorphism modifies the AAO of HD.

Published 2 April 2008 in Hum Mol Genet, 17(8): 1137-46.
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Articles on Huntington's Disease published 13 March 2008:

N-terminal mutant huntingtin associates with mitochondria and impairs mitochondrial trafficking.   J Neurosci, 28(11): 2783-92.

Huntington's disease (HD) is caused by polyglutamine (polyQ) expansion in huntingtin (htt), a large (350 kDa) protein that localizes predominantly to the cytoplasm. Proteolytic cleavage of mutant htt yields polyQ-containing N-terminal fragments that are prone to misfolding and aggregation. Disease progression in HD transgenic models correlates with age-related accumulation of soluble and aggregated forms of N-terminal mutant htt fragments, suggesting that multiple forms of mutant htt are ... [Abstract] [Full-text]

Articles on Huntington's Disease published 3 March 2008:

Stem cell factor and mesenchymal and neural stem cell transplantation in a rat model of Huntington's disease.   Mol Cell Neurosci, 37(3): 454-70.

Neural and mesenchymal stem cells have been proposed as alternative sources of cells for transplantation into the brain in neurodegenerative disorders. However, the endogenous factors controlling their engraftment within the injured parenchyma remain ill-defined. Here, we demonstrate significant engraftment of undifferentiated exogenous mesenchymal or neural stem cells throughout the lesioned area in a rat model for Huntington's disease, as late as 8 weeks post-transplantation. We show that ... [Abstract] [Full-text]

Articles on Huntington's Disease published 18 February 2008:

Excitotoxic neuronal death and the pathogenesis of Huntington's disease.   Arch Med Res, 39(3): 265-76.

Huntington's disease (HD) is a neurodegenerative hereditary illness originated by the mutation of the gene encoding the huntingtin-protein (htt). Mutated htt (mhtt) is characterized by an increased number of glutamine repeats in the N-terminal end; when 40 or more glutamine residues are present, the disease is manifested. Expression of mhtt leads to the selective death of the medium spiny neurons (MSN) in the neostriatum, resulting in the appearance of generalized involuntary movements, the ... [Abstract] [Full-text]

Articles on Huntington's Disease published 29 January 2008:

"You're one of us now": young people describe their experiences of predictive genetic testing for Huntington disease (HD) and familial adenomatous polyposis (FAP).   Am J Med Genet C Semin Med Genet, 148(1): 47-55.

There has been much debate about the psychosocial effects of predictive genetic testing in minors. The majority of this debate has been theoretical, with little empirical evidence published. We conducted in-depth interviews with 18 young people who had undergone testing, to explore the range of harms and benefits that they perceived were associated with their tests. Participants were eight individuals who were tested for Huntington disease (two gene-positive, six gene-negative) and ten who were ... [Abstract] [Full-text]

Articles on Huntington's Disease published 28 January 2008:

The impact of neurological illness on marital relationships.   J Sex Marital Ther, 34(2): 115-32.

The current study investigated the impact of neurological illness on marital relationship satisfaction. Participants numbered 423 patients and 335 carers from motor neurone disease (MND), Huntington's disease (HD), Parkinson's, and multiple sclerosis (MS). The results demonstrated that patients and carers with HD had a significantly lower level of relationship satisfaction and sex life satisfaction than the other three illness groups. Further, patients with HD indicated a significantly higher ... [Abstract] [Full-text]

Articles on Huntington's Disease published 18 January 2008:

Longitudinal analysis of regional grey matter loss in Huntington disease: effects of the length of the expanded CAG repeat.   J Neurol Neurosurg Psychiatry, 79(2): 130-5.

BACKGROUND: The mechanisms guiding the progression of neuronal damage in patients with Huntington disease (HD) are not completely understood. It is unclear whether the genotype--that is, the length of the expanded CAG repeat--guides the location and speed of grey matter decline once HD is clinically manifested. Moreover, the relationship between cortical and subcortical grey matter atrophy and the severity of motor symptoms of HD is controversial. OBJECTIVES: In this article, we longitudinally ... [Abstract] [Full-text]

Articles on Huntington's Disease published 17 January 2008:

Sensitive biochemical aggregate detection reveals aggregation onset before symptom development in cellular and murine models of Huntington's disease.   J Neurochem, 104(3): 846-58.

A CAG-repeat gene expansion translated into a pathogenic polyglutamine stretch at the N-terminus of huntingtin triggers Huntington's Disease. Mutated huntingtin is predicted to adopt toxic properties mainly if aggregation-prone N-terminal fragments are released by proteolysis. Huntingtin-aggregates are indeed a major hallmark of this disorder and could represent useful markers of disease-onset or progression. We designed a simple method for qualitative and quantitative characterization of ... [Abstract] [Full-text]

Articles on Huntington's Disease published 11 December 2007:

Huntington's disease affects movement termination.   Behav Brain Res, 187(1): 153-8.

Huntington's disease (HD) is a neurodegenerative disease affecting the striatum and associated with deficits in voluntary movement in early stages. The final portion of aiming movements is particularly affected in HD and one hypothesis is that this deficit is linked to attention or terminal control requirements. Sixteen patients with early HD and 16 age-matched controls were examined in aiming movements. Four conditions manipulated movement termination requirements (discrete movements with a ... [Abstract] [Full-text]

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