scholarly journals Special Issue: DNA Repair and Somatic Repeat Expansion in Huntington’s Disease

2021 ◽  
Vol 10 (1) ◽  
pp. 3-5
Author(s):  
Lesley Jones ◽  
Vanessa C. Wheeler ◽  
Christopher E. Pearson
Keyword(s):  
Dna Repair ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Repeat Expansion ◽  
Special Issue

Borderline repeat expansion in Huntington's disease

The Lancet ◽  
1993 ◽  
Vol 342 (8885) ◽  
pp. 1491-1492 ◽  
Author(s):  
K.E de Rooij ◽  
P.A.M de Koning Gans ◽  
M Losekoot ◽  
E Bakker ◽  
J.T den Dunnen ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Repeat Expansion

scholarly journals MSH3 modifies somatic instability and disease severity in Huntington’s and myotonic dystrophy type 1

Brain ◽  
2019 ◽  
Vol 142 (7) ◽  
pp. 1876-1886 ◽  
Author(s):  
Michael Flower ◽  
Vilija Lomeikaite ◽  
Marc Ciosi ◽  
Sarah Cumming ◽  
Fernando Morales ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Association Study ◽  
Huntington’S Disease ◽  
Myotonic Dystrophy ◽  
Disease Onset ◽  
Repeat Expansion ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type ◽  
Exon 1

Abstract The mismatch repair gene MSH3 has been implicated as a genetic modifier of the CAG·CTG repeat expansion disorders Huntington’s disease and myotonic dystrophy type 1. A recent Huntington’s disease genome-wide association study found rs557874766, an imputed single nucleotide polymorphism located within a polymorphic 9 bp tandem repeat in MSH3/DHFR, as the variant most significantly associated with progression in Huntington’s disease. Using Illumina sequencing in Huntington’s disease and myotonic dystrophy type 1 subjects, we show that rs557874766 is an alignment artefact, the minor allele for which corresponds to a three-repeat allele in MSH3 exon 1 that is associated with a reduced rate of somatic CAG·CTG expansion (P = 0.004) and delayed disease onset (P = 0.003) in both Huntington’s disease and myotonic dystrophy type 1, and slower progression (P = 3.86 × 10−7) in Huntington’s disease. RNA-Seq of whole blood in the Huntington’s disease subjects found that repeat variants are associated with MSH3 and DHFR expression. A transcriptome-wide association study in the Huntington’s disease cohort found increased MSH3 and DHFR expression are associated with disease progression. These results suggest that variation in the MSH3 exon 1 repeat region influences somatic expansion and disease phenotype in Huntington’s disease and myotonic dystrophy type 1, and suggests a common DNA repair mechanism operates in both repeat expansion diseases.

scholarly journals Conformational studies of pathogenic expanded polyglutamine protein deposits from Huntington’s disease

2019 ◽  
Vol 244 (17) ◽  
pp. 1584-1595 ◽  
Author(s):  
Irina Matlahov ◽  
Patrick CA van der Wel
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Structural Biology ◽  
Age Of Onset ◽  
Repeat Expansion ◽  
Cag Repeat ◽  
Mutant Huntingtin ◽  
Cag Repeat Expansion ◽  
Recent Developments ◽  
Mutant Huntingtin Protein

Huntington’s disease, like other neurodegenerative diseases, continues to lack an effective cure. Current treatments that address early symptoms ultimately fail Huntington’s disease patients and their families, with the disease typically being fatal within 10–15 years from onset. Huntington’s disease is an inherited disorder with motor and mental impairment, and is associated with the genetic expansion of a CAG codon repeat encoding a polyglutamine-segment-containing protein called huntingtin. These Huntington’s disease mutations cause misfolding and aggregation of fragments of the mutant huntingtin protein, thereby likely contributing to disease toxicity through a combination of gain-of-toxic-function for the misfolded aggregates and a loss of function from sequestration of huntingtin and other proteins. As with other amyloid diseases, the mutant protein forms non-native fibrillar structures, which in Huntington’s disease are found within patients’ neurons. The intracellular deposits are associated with dysregulation of vital processes, and inter-neuronal transport of aggregates may contribute to disease progression. However, a molecular understanding of these aggregates and their detrimental effects has been frustrated by insufficient structural data on the misfolded protein state. In this review, we examine recent developments in the structural biology of polyglutamine-expanded huntingtin fragments, and especially the contributions enabled by advances in solid-state nuclear magnetic resonance spectroscopy. We summarize and discuss our current structural understanding of the huntingtin deposits and how this information furthers our understanding of the misfolding mechanism and disease toxicity mechanisms. Impact statement Many incurable neurodegenerative disorders are associated with, and potentially caused by, the amyloidogenic misfolding and aggregation of proteins. Usually, complex genetic and behavioral factors dictate disease risk and age of onset. Due to its principally mono-genic origin, which strongly predicts the age-of-onset by the extent of CAG repeat expansion, Huntington’s disease (HD) presents a unique opportunity to dissect the underlying disease-causing processes in molecular detail. Yet, until recently, the mutant huntingtin protein with its expanded polyglutamine domain has resisted structural study at the atomic level. We present here a review of recent developments in HD structural biology, facilitated by breakthrough data from solid-state NMR spectroscopy, electron microscopy, and complementary methods. The misfolded structures of the fibrillar proteins inform our mechanistic understanding of the disease-causing molecular processes in HD, other CAG repeat expansion disorders, and, more generally, protein deposition disease.

Correlations Between Triplet Repeat Expansion and Clinical Features in Huntington's Disease

1995 ◽  
Vol 52 (8) ◽  
pp. 749-753 ◽  
Author(s):  
S. Claes ◽  
K. Van Zand ◽  
E. Legius ◽  
R. Dom ◽  
M. Malfroid ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Clinical Features ◽  
Repeat Expansion ◽  
Triplet Repeat ◽  
Triplet Repeat Expansion

scholarly journals New developments in Huntington’s disease and other triplet repeat diseases: DNA repair turns to the dark side

2020 ◽  
Vol 4 (4) ◽  
Author(s):  
Robert S. Lahue
Keyword(s):  
Dna Repair ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Cag Repeat ◽  
Model Systems ◽  
Triplet Repeat ◽  
Maximal Effect ◽  
Huntingtin Protein ◽  
Dna Repair Proteins ◽  
Repeat Expansions

Abstract Huntington’s disease (HD) is a fatal, inherited neurodegenerative disease that causes neuronal death, particularly in medium spiny neurons. HD leads to serious and progressive motor, cognitive and psychiatric symptoms. Its genetic basis is an expansion of the CAG triplet repeat in the HTT gene, leading to extra glutamines in the huntingtin protein. HD is one of nine genetic diseases in this polyglutamine (polyQ) category, that also includes a number of inherited spinocerebellar ataxias (SCAs). Traditionally it has been assumed that HD age of onset and disease progression were solely the outcome of age-dependent exposure of neurons to toxic effects of the inherited mutant huntingtin protein. However, recent genome-wide association studies (GWAS) have revealed significant effects of genetic variants outside of HTT. Surprisingly, these variants turn out to be mostly in genes encoding DNA repair factors, suggesting that at least some disease modulation occurs at the level of the HTT DNA itself. These DNA repair proteins are known from model systems to promote ongoing somatic CAG repeat expansions in tissues affected by HD. Thus, for triplet repeats, some DNA repair proteins seem to abandon their normal genoprotective roles and, instead, drive expansions and accelerate disease. One attractive hypothesis—still to be proven rigorously—is that somatic HTT expansions augment the disease burden of the inherited allele. If so, therapeutic approaches that lower levels of huntingtin protein may need blending with additional therapies that reduce levels of somatic CAG repeat expansions to achieve maximal effect.

scholarly journals Striatal Circuit Development and Its Alterations in Huntington’s Disease

2020 ◽  
Author(s):  
Margaux Lebouc ◽  
Quentin Richard ◽  
Maurice Garret ◽  
Jérôme Baufreton
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mouse Models ◽  
Neurodegenerative Disorder ◽  
Repeat Expansion ◽  
Cag Repeat ◽  
Rodent Models ◽  
Network Development ◽  
Cag Repeat Expansion ◽  
Circuit Development

Huntington's disease (HD) is an inherited neurodegenerative disorder that usually starts during midlife with progressive alterations of motor and cognitive functions. The disease is caused by a CAG repeat expansion within the huntingtin gene leading to severe striatal neurodegeneration. Recent studies conducted on pre-HD children highlight early striatal developmental alterations starting as soon as 6 years old, the earliest age assessed. These findings, in line with data from mouse models of HD, raise the question of when during development do the first disease-related striatal alterations emerge or whether they contribute to the later appearance of the neurodegenerative features of the disease. In this review we will describe the different stages of striatal network development and then discuss recent evidence for its alterations in rodent models of the disease. We argue that a better understanding of the striatum’s development should help in assessing aberrant neurodevelopmental processes linked to the HD mutation.

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