Localization and function of the Drosophila huntingtin protein

Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Biology, 2007."September 3, 2007."Includes bibliographical references (p. 34-40).Huntington's Disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expansion of a polyglutamine tract in the huntingtin protein. This mutation leads to conformational instability, resulting in huntingtin aggregation and degeneration of neurons in the striatum and cortex. HD is characterized by motor dysfunction, personality changes, dementia, and early death. Although a number of abnormal cellular phenomena have been described in systems modeling HD, the specific events initiating pathology remain unclear. It is widely viewed that inclusions may have a toxic gain-of-function which is central to HD pathogenesis. However, evidence is accumulating that supports the loss of huntingtin function as a likely contributor to the unraveling of cellular processes early in the course of the disease. The fruit fly Drosophila melanogaster has an orthologous huntingtin gene with several regions showing 40-50% similarity to mammalian huntingtin at the amino acid level. Like the mammalian huntingtin gene, the fly huntingtin lacks sequence motifs that would suggest functional correlates to other known proteins. I have pursued a cell biological and physiological analysis of Drosophila melanogaster mutants with reduced huntingtin gene expression. Normal levels of huntingtin were not required for normal localization of mitochondria in neurons, synaptic transmission in the visual system, or formation of synapses.by James D. Mediatore.S.M

Oxidative stress parameters in plasma of Huntington's disease patients, asymptomatic Huntington's disease gene carriers and healthy subjects : a cross-sectional study

BACKGROUND : Animal data and postmortem studies suggest a role of oxidative stress in the Huntington's disease (HD), but in vivo human studies have been scarce. ----- AIM : To assess the presence of oxidative stress in HD patients and its occurrence relative to clinical symptoms. ----- METHODS : Oxidative stress markers were determined in plasma of HD patients (n = 19), asymptomatic HD gene carriers (with > 38 CAG repeats) (n = 11) and their respective sex and agematched healthy controls (n = 47 and n = 22) in a cross-sectional study. ----- RESULTS : With adjustment for age and sex, HD patients had higher plasma lipid peroxidation (LP) levels (ratio 1.20, 95% CI 1.09 to 1.32, p < 0.001) and lower reduced glutathione (GSH) levels (ratio 0.72, CI 0.55 to 0.94, p = 0.011) than their age and sex-matched controls. Although considerably younger, HD gene carriers did not differ from HD patients regarding LP and GSH levels, and had higher plasma LP (ratio 1.16, CI 1.02 to 1.32, p = 0.016) and lower GSH than their matched controls (ratio 0.73, CI 0.5 to 1.05). They had higher LP (ratio 1.18, CI 1.02 to 1.34, p = 0.019) and lower GSH (ratio 0.75, CI 0.51 to 1.11) than the healthy subjects matched to HD patients. ----- CONCLUSIONS : Oxidative stress is more pronounced in HD patients and asymptomatic HD gene carriers than in healthy subjects. Differences in plasma LP and GSH are in line with the brain findings in animal models of HD. Data suggest that oxidative stress occurs before the onset of the HD symptoms

Characterization, developmental expression and evolutionary features of the huntingtin gene in the amphioxus Branchiostoma floridae

<p>Abstract</p> <p>Background</p> <p>Huntington's disease is an inherited neurodegenerative disorder that is caused by the expansion of an N-terminal polyQ stretch in the huntingtin protein. In order to investigate the hypothesis that huntingtin was already involved in development of the nervous system in the last common ancestor of chordates, we isolated and characterised the huntingtin homologue from the amphioxus <it>Branchiostoma floridae</it>. In the present paper the amphioxus general term must be referred to <it>Branchiostoma floridae</it>.</p> <p>Results</p> <p>In this report, we show that the exon-intron organization of the amphioxus huntingtin gene is highly conserved with that of other vertebrates species. The AmphiHtt protein has two glutamine residues in the position of the typical vertebrate polyQ tract. Sequence conservation is greater along the entire length of the protein than in a previously identified <it>Ciona </it>huntingtin. The first three N-terminal HEAT repeats are highly conserved in vertebrates and amphioxus, although exon rearrangement has occurred in this region. <it>AmphiHtt </it>expression is detectable by in situ hybridization starting from the early neurula stage, where it is found in cells of the neural plate. At later stages, it is retained in the neural compartment but also it appears in limited and well-defined groups of non-neural cells. At subsequent larval stages, <it>AmphiHtt </it>expression is detected in the neural tube, with the strongest signal being present in the most anterior part.</p> <p>Conclusion</p> <p>The cloning of amphioxus huntingtin allows to infer that the polyQ in huntingtin was already present 540 million years ago and provides a further element for the study of huntingtin function and its evolution along the deuterostome branch.</p

Ancient origin of the CAG expansion causing Huntington disease in a Spanish population

25 p. Figuras, tablas, bibliografíaHuntington disease (HD, MIM# 143100) is an autosomal dominant neurodegenerative disorder characterized clinically by progressive motor impairment, cognitive decline, and emotional deterioration. The disease is caused by the abnormal expansion of a CAG trinucleotide repeat in the first exon of the huntingtin gene in chromosome 4p16.3. HD is spread worldwide and it is generally accepted that few mutational events account for the origin of the pathogenic CAG expansion in most populations. We have investigated the genetic history of HD mutation in 83 family probands from the Land of Valencia, Eastern Spain. An analysis of the HD/CCG repeat in informative families suggested that at least two main chromosomes were associated in the Valencian population, one associated with allele 7 (77 mutant chromosomes) and one associated with allele 10 (2 mutant chromosomes). Haplotype A-7-A (H1) was observed in 47 out of 48 phase-known mutant chromosomes, obtained by segregation analysis, through the haplotype analysis of rs1313770-HD/CCGrs82334, as it also was in 120 out of 166 chromosomes constructed by means of the PHASE program. The genetic history and geographical distribution of the main haplotype H1 were both studied by constructing extended haplotypes with flanking STRs D4S106 and D4S3034. We found that we were able to determine the age of the CAG expansion associated with the haplotype H1 as being between 4,700 and 10,000 years ago. Furthermore, we observed a nonhomogenous distribution in the different regions associated with the different extended haplotypes of the ancestral haplotype H1, suggesting that local founder effects have occurred.This work was supported by the Fondo de investigación Sanitaria (FIS grant 01/1159), the Instituto de Salud Carlos III (grant G03/56) for the Spanish Network on Cerebellar Ataxias, and the Generalitat Valenciana (grant GRUPOS03/015).Peer reviewe

Letter to the editor: autoimmune pathogenic mechanisms in Huntington’s disease

Letter to the Editor: Autoimmune pathogenic mechanisms in Huntington's disease