The association of CAG repeat length with clinical progression in Huntington disease

Rosenblatt, Adam; Liang, Kung Yee; Zhou, Hufang; Abbott, Margaret H.; Gourley, Lisa M.; Margolis, Russell L.; Brandt, Jason; Ross, Christopher A.

doi:10.1212/01.wnl.0000204230.16619.d9

Cited by 127 publications

(99 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…7 In the present studies, we show that 3B5H10 reacts in situ with Htt exon-1 76Q, the PGQ 9 ␤-turn former, and the ␤-strand-alternating PGQ 6/12 protein. 3B5H10 reactivity was slightly higher for the PGQ 6/12 protein than for PGQ 9 ␤-turn former.…”

Section: Discussionsupporting

confidence: 56%

“…Normal length polyQ regions vary between 10 and 25 residues, while longer repeats of 36 glutamines or more can cause HD (6). Clinical studies in HD patients have shown that a longer repeat results in an earlier age of onset and a more rapid disease progression (7,8). Based on more recent work, Htt is thought to undergo several proteolytic cleavage events, resulting in a number of Htt truncation products (9,10).…”

mentioning

confidence: 99%

See 1 more Smart Citation

A Compact β Model of huntingtin Toxicity

Zhang¹,

Yeh²,

Leyva³

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Huntington disease results from an expanded polyglutamine region in the N terminus of the huntingtin protein. HD pathology is characterized by neuronal degeneration and protein inclusions containing N-terminal fragments of mutant huntingtin. Structural information is minimal, though it is believed that mutant huntingtin polyglutamine adopts ␤ structure upon conversion to a toxic form. To this end, we designed mammalian cell expression constructs encoding compact ␤ variants of Htt exon 1 N-terminal fragment and tested their ability to aggregate and induce toxicity in cultured neuronal cells. In parallel, we performed molecular dynamics simulations, which indicate that constructs with expanded polyglutamine ␤-strands are stabilized by main-chain hydrogen bonding. Finally, we found a correlation between the reactivity to 3B5H10, an expanded polyglutamine antibody that recognizes a compact ␤ rich hairpin structure, and the ability to induce cell toxicity. These data are consistent with an important role for a compact ␤ structure in mutant huntingtin-induced cell toxicity.

show abstract

Section: Discussionsupporting

confidence: 56%

mentioning

confidence: 99%

A Compact β Model of huntingtin Toxicity

Zhang¹,

Yeh²,

Leyva³

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Another aspect that should be highlighted is that longer CAG repeat length may have a small effect on rate of disease progression 22 , so one should expect a slightly less favorable outcome among our patients with non-choreic movement disorders as their motor presentation of HD. Unfortunately, our study had the limitation of not having a longitudinal design and this hypothesis cannot be inferred at this time.…”

Section: Discussionmentioning

confidence: 99%

Non-choreic movement disorders as initial manifestations of Huntington's disease

Becker

Munhoz

Raskin

et al. 2007

Arq. Neuro-Psiquiatr.

View full text Add to dashboard Cite

Huntington's disease (HD) is an autosomal dominantly inherited, progressive, neurodegenerative disorder characterized by cognitive decline, psychiatric disturbances, and involuntary movements -classically choreic. Symptoms usually present with slow progression leading to dementia and death approximately 15-20 years after disease onset 1 . Symptoms begin insidiously, most commonly between the ages of 35 and 50 years, with substantial variation that depends, in part, on the CAG repeat expansion length 1 . Chorea, or choreoathetosis, is the movement disorder most frequently associated with HD, although some individuals may exhibit other forms of motor symptoms as their initial presentation 1,6,7 .We describe the clinical features of a cohort of Brazilian HD patients who initially presented with movement disorders other than chorea. We also investigate the correlation of the clinical profile of this subgroup with their respective CAG expansion length in comparison with "typical" choreic HD patients. METHODWe evaluated 44 individuals from a total of 30 families followed at the Movement Disorders Unit from 1996 to 2000 with final diagnosis of HD. All patients presented motor symptoms as their initial manifestation of the disorder and were assessed by the same author (NB) using ABSTRACT -We describe seven patients with genetically confirmed Huntington's disease (HD) who had non-choreic movement disorders as presenting symptoms or signs. Patients with movement disorders other than chorea in the early stages tended to have larger CAG trinucleotide repeat expansion in comparison with more "typical" HD patients.

show abstract

“…Individuals affected with HD have a polyQ region of 36 or more glutamine residues (4), and clinical studies have shown an inverse correlation between polyQ length and age of disease onset (5,6). Recent work indicates that Htt may undergo proteolysis, generating several truncation products (7,8).…”

mentioning

confidence: 99%

Identification of Novel Potentially Toxic Oligomers Formed in Vitro from Mammalian-derived Expanded huntingtin Exon-1 Protein

Nucifora

Burke

Feng

et al. 2012

Journal of Biological Chemistry

103

105

View full text Add to dashboard Cite

Huntington disease is a genetic neurodegenerative disorder that arises from an expanded polyglutamine region in the N terminus of the HD gene product, huntingtin. Protein inclusions comprised of N-terminal fragments of mutant huntingtin are a characteristic feature of disease, though are likely to play a protective role rather than a causative one in neurodegeneration. Soluble oligomeric assemblies of huntingtin formed early in the aggregation process are candidate toxic species in HD. In the present study, we established an in vitro system to generate recombinant huntingtin in mammalian cells. Using both denaturing and native gel analysis, we have identified novel oligomeric forms of mammalian-derived expanded huntingtin exon-1 N-terminal fragment. These species are transient and were not previously detected using bacterially expressed exon-1 protein. Importantly, these species are recognized by 3B5H10, an antibody that recognizes a two-stranded hairpin conformation of expanded polyglutamine believed to be associated with a toxic form of huntingtin. Interestingly, comparable oligomeric species were not observed for expanded huntingtin shortstop, a 117-amino acid fragment of huntingtin shown previously in mammalian cell lines and transgenic mice, and here in primary cortical neurons, to be non-toxic. Further, we demonstrate that expanded huntingtin shortstop has a reduced ability to form amyloid-like fibrils characteristic of the aggregation pathway for toxic expanded polyglutamine proteins. Taken together, these data provide a possible candidate toxic species in HD. In addition, these studies demonstrate the fundamental differences in early aggregation events between mutant huntingtin exon-1 and shortstop proteins that may underlie the differences in toxicity. Huntington disease (HD)3 is an inherited neurodegenerative disorder caused by an expanded polyglutamine (polyQ) region in the N terminus of the HD gene product, huntingtin (htt), a large protein over 3,000 amino acids in length (1-3). Individuals affected with HD have a polyQ region of 36 or more glutamine residues (4), and clinical studies have shown an inverse correlation between polyQ length and age of disease onset (5, 6). Recent work indicates that Htt may undergo proteolysis, generating several truncation products (7,8). One of the smallest products is an N-terminal fragment that corresponds to the first exon of the HD gene and is comprised of the first 90 amino acids of Htt (based on a polyQ region of 23 glutamine repeats (3)). Htt exon-1 is of particular interest, as it is believed to be a mediator of toxicity in animal models of HD and in HD patients.HD is characterized by the deposition of large intracellular protein aggregates, or inclusion bodies, comprised of N-terminal fragments of mutant Htt. In HD, there is a strong correlation between polyQ repeat length and the threshold for aggregation and disease (4). While inclusions are a pathological hallmark of disease, inclusion formation does not correlate well with pathogenesis in vivo (9 -12). ...

show abstract

The association of CAG repeat length with clinical progression in Huntington disease

Abstract: CAG repeat length has a small effect on rate of progression that may be clinically important over time. Individuals with the shortest expansions appear to have the best prognosis. These effects of the CAG length may be relevant in the analysis of clinical trials.

Cited by 127 publications

References 30 publications

A Compact β Model of huntingtin Toxicity

A Compact β Model of huntingtin Toxicity

Non-choreic movement disorders as initial manifestations of Huntington's disease

Identification of Novel Potentially Toxic Oligomers Formed in Vitro from Mammalian-derived Expanded huntingtin Exon-1 Protein

Contact Info

Product

Resources

About