Promotion of somatic CAG repeat expansion by Fan1 knock-out in Huntington’s disease knock-in mice is blocked by Mlh1 knock-out

Abstract Recent genome-wide association studies of age-at-onset in Huntington’s disease (HD) point to distinct modes of potential disease modification: altering the rate of somatic expansion of the HTT CAG repeat or altering the resulting CAG threshold length-triggered toxicity process. Here, we evaluated the mouse orthologs of two HD age-at-onset modifier genes, FAN1 and RRM2B, for an influence on somatic instability of the expanded CAG repeat in Htt CAG knock-in mice. Fan1 knock-out increased somatic expansion of Htt CAG repeats, in the juvenile- and the adult-onset HD ranges, whereas knock-out of Rrm2b did not greatly alter somatic Htt CAG repeat instability. Simultaneous knock-out of Mlh1, the ortholog of a third HD age-at-onset modifier gene (MLH1), which suppresses somatic expansion of the Htt knock-in CAG repeat, blocked the Fan1 knock-out-induced acceleration of somatic CAG expansion. This genetic interaction indicates that functional MLH1 is required for the CAG repeat destabilizing effect of FAN1 loss. Thus, in HD, it is uncertain whether the RRM2B modifier effect on timing of onset may be due to a DNA instability mechanism. In contrast, the FAN1 modifier effects reveal that functional FAN1 acts to suppress somatic CAG repeat expansion, likely in genetic interaction with other DNA instability modifiers whose combined effects can hasten or delay onset and other CAG repeat length-driven phenotypes.

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The platelet maximum number of A2A-receptor binding sites (Bmax) linearly correlates with age at onset and CAG repeat expansion in Huntington's disease patients with predominant chorea

Neuroscience Letters ◽

10.1016/j.neulet.2005.09.037 ◽

2006 ◽

Vol 393 (1) ◽

pp. 27-30 ◽

Cited By ~ 25

Author(s):

Vittorio Maglione ◽

Milena Cannella ◽

Tiziana Martino ◽

Antonio De Blasi ◽

Luigi Frati ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Receptor Binding ◽

Binding Sites ◽

Age At Onset ◽

Repeat Expansion ◽

Cag Repeat ◽

Cag Repeat Expansion ◽

A2a Receptor

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FAN1 nuclease activity affects CAG expansion and age at onset of Huntington’s disease

10.1101/2021.04.13.439716 ◽

2021 ◽

Author(s):

Branduff McAllister ◽

Jasmine Donaldson ◽

Caroline S. Binda ◽

Sophie Powell ◽

Uroosa Chughtai ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Cell Model ◽

Association Studies ◽

Age At Onset ◽

Nuclease Activity ◽

Cag Repeat ◽

Genome Wide Association Studies ◽

Knock Out ◽

Cag Expansion

SummaryThe age at onset of motor symptoms in Huntington’s disease (HD) is driven by HTT CAG repeat length but modified by other genes. We used exome sequencing of 683 HD patients with extremes of onset or phenotype relative to CAG length to identify rare variants associated with clinical effect. We identified damaging coding variants in candidate modifier genes from prior genome-wide association studies associated with altered HD onset or severity. Variants in FAN1 clustered in its DNA-binding and nuclease domains and were associated predominantly with earlier onset HD. Nuclease activities of these variants correlated with residual age at motor onset of HD. Mutating endogenous FAN1 to a nuclease-inactive form in an induced pluripotent stem cell model of HD led to rates of CAG expansion comparable to those observed with complete FAN1 knock out. Together, these data implicate FAN1 nuclease activity in slowing somatic repeat expansion and hence onset of HD.

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

Experimental Biology and Medicine ◽

10.1177/1535370219856620 ◽

2019 ◽

Vol 244 (17) ◽

pp. 1584-1595 ◽

Cited By ~ 3

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.

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Striatal Circuit Development and Its Alterations in Huntington’s Disease

10.20944/preprints202005.0488.v1 ◽

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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