A disorder similar to Huntington's disease is associated with a novel CAG repeat expansion

2001 ◽  
Vol 50 (3) ◽  
pp. 373-380 ◽  
Author(s):  
Russell L. Margolis ◽  
Elizabeth O'Hearn ◽  
Adam Rosenblatt ◽  
Virginia Willour ◽  
Susan E. Holmes ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Repeat Expansion ◽  
Cag Repeat ◽  
Cag Repeat Expansion

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.

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.

scholarly journals FAN1 controls mismatch repair complex assembly via MLH1 retention to stabilize CAG repeat expansion in Huntington’s disease

Cell Reports ◽  
2021 ◽  
Vol 36 (9) ◽  
pp. 109649
Author(s):  
Robert Goold ◽  
Joseph Hamilton ◽  
Thomas Menneteau ◽  
Michael Flower ◽  
Emma L. Bunting ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mismatch Repair ◽  
Repeat Expansion ◽  
Cag Repeat ◽  
Complex Assembly ◽  
Cag Repeat Expansion

A disorder similar to Huntington's disease is associated with a novel CAG repeat expansion

2001 ◽  
Vol 50 (6) ◽  
pp. 373-380 ◽  
Author(s):  
Russell L. Margolis ◽  
Elizabeth O'Hearn ◽  
Adam Rosenblatt ◽  
Virginia Willour ◽  
Susan E. Holmes ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Repeat Expansion ◽  
Cag Repeat ◽  
Cag Repeat Expansion

Repeat expansion and autosomal dominant neurodegenerative disorders: consensus and controversy

2003 ◽  
Vol 5 (21) ◽  
pp. 1-24 ◽  
Author(s):  
Dobrila D. Rudnicki ◽  
Russell L. Margolis
Keyword(s):  
Calcium Channel ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorders ◽  
Autosomal Dominant ◽  
Muscular Atrophy ◽  
Early Stage ◽  
Repeat Expansion ◽  
Cag Repeat ◽  
Cag Repeat Expansion

Repeat-expansion mutations cause 13 autosomal dominant neurodegenerative disorders falling into three groups. Huntington's disease (HD), dentatorubral pallidoluysian atrophy (DRPLA), spinal and bulbar muscular atrophy (SBMA), and spinocerebellar ataxias (SCAs) types 1, 2, 3, 7 and 17 are each caused by a CAG repeat expansion that encodes polyglutamine. Convergent lines of evidence demonstrate that neurodegeneration in these diseases is a consequence of the neurotoxic effects of abnormally long stretches of glutamines. How polyglutamine induces neurodegeneration, and why neurodegeneration occurs in only select neuronal populations, remains a matter of intense investigation. SCA6 is caused by a CAG repeat expansion in CACNA1A, a gene that encodes a subunit of the P/Q-type calcium channel. The threshold length at which the repeat causes disease is much shorter than in the other polyglutamine diseases, and neurodegeneration may arise from expansion-induced change of function in the calcium channel. Huntington's disease-like 2 (HDL2) and SCAs 8, 10 and 12 are rare disorders in which the repeats (CAG, CTG or ATTCT) are not in protein-coding regions. Investigation into these diseases is still at an early stage, but it is now reasonable to hypothesise that the net effect of each expansion is to alter gene expression. The different pathogenic mechanisms in these three groups of diseases have important implications for the development of rational therapeutics.

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