CAG repeat lengths ≥ 335 attenuate the phenotype in the R6/2 Huntington's disease transgenic mouse

Dragatsis, Ioannis; Goldowitz, Dan; Mar, Nobel Del; Deng, Yunping; Meade, Christopher A.; Liu, Li; Sun, Zhiqiang; Dietrich, Paula; Yue, Junming; Reiner, Anton

doi:10.1016/j.nbd.2008.10.009

Cited by 69 publications

(86 citation statements)

References 119 publications

(203 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3a, b). Together with previous reports showing that mRNA levels of mutant HTT decrease with increasing repeat lengths in HD mouse models 31,32 , these data support the hypothesis that an expanded CAG repeat increases the translation efficiency of mutant HTT mRNA in vivo.…”

Section: Mid1supporting

confidence: 87%

Translation of HTT mRNA with expanded CAG repeats is regulated by the MID1–PP2A protein complex

et al. 2013

View full text Add to dashboard Cite

Expansion of CAG repeats is a common feature of various neurodegenerative disorders, including Huntington's disease. Here we show that expanded CAG repeats bind to a translation regulatory protein complex containing MID1, protein phosphatase 2A and 40S ribosomal S6 kinase. Binding of the MID1-protein phosphatase 2A protein complex increases with CAG repeat size and stimulates translation of the CAG repeat expansion containing messenger RNA in a MID1-, protein phosphatase 2A-and mammalian target of rapamycindependent manner. Our data indicate that pathological CAG repeat expansions upregulate protein translation leading to an overproduction of aberrant protein and suggest that the MID1-complex may serve as a therapeutic target for the treatment of CAG repeat expansion disorders.

show abstract

Section: Mid1supporting

confidence: 87%

Translation of HTT mRNA with expanded CAG repeats is regulated by the MID1–PP2A protein complex

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Surprisingly, some neurological symptoms and a lifespan are greatly ameliorated in R6/2 mice carrying more than 200 CAG repeat expansions [47][48][49]. These unexpected results can be explained by transgene expression decrease observed in these mice [48]. A spontaneous contraction from 116 to ∼89 CAG repeat was described in R6/1 mice [50].…”

Section: R6 Transgenic Mouse Linesmentioning

confidence: 94%

“…The size of CAG repeat is positively correlated with the severity of symptoms up to ∼160 CAG repeats [47]. Surprisingly, some neurological symptoms and a lifespan are greatly ameliorated in R6/2 mice carrying more than 200 CAG repeat expansions [47][48][49]. These unexpected results can be explained by transgene expression decrease observed in these mice [48].…”

Section: R6 Transgenic Mouse Linesmentioning

confidence: 94%

“…In R6/2 mice, the size of transmitted CAG expansion increases with the age of transmitting males [45]. A selective R6/2 breeding enabled to obtain numerous R6/2 colonies with inheriting CAG repeat ranging from ∼110 to 450 [47][48][49]. The size of CAG repeat is positively correlated with the severity of symptoms up to ∼160 CAG repeats [47].…”

Section: R6 Transgenic Mouse Linesmentioning

confidence: 99%

“…In R6/2 mice, the somatic mosaicism is correlated with the transmitted CAG repeat size but the somatic variation is not linear, particularly in striatum [52]. Interestingly, the frequency of CAG contractions increases in brain tissues and liver from mice with more than 500 CAG repeats [52] and could also explain the progressive reduction of neurological symptoms and prolonged lifespan in R6/2 mice with >200 CAG repeats [47][48][49]. Somatic instability has been noticed in dividing cells suggesting a role of DNA replication in the dynamic of triplet repeat instability.…”

Section: R6 Transgenic Mouse Linesmentioning

confidence: 99%

See 2 more Smart Citations

Genetic Modifiers of CAG.CTG Repeat Instability in Huntington's Disease Mouse Models

Dandelot¹,

Tomé²

2017

Huntington's Disease - Molecular Pathogenesis and Current Models

View full text Add to dashboard Cite

Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder whose characterstics were first described by George Huntington in 1872. Several decades later, in 1993, the mutation behind this disease was found to be an unstable expanded CAG repeat within exon 1 of the HTT gene localized on the short arm of chromosome 4. The majority of HD patients carry more than 40 CAG repeats, which become unstable and usually increase in size in successive generations and in tissues. In order to dissect the molecular mechanisms underlying CAG repeat instability, several HD mouse models have been created in the 1990s. Significant data have revealed that the absence of proteins from the mismatch repair (MMR) or the base and nucleotide excision repair decreased the pathogenic expansion-biased somatic mosaicism and/or intergenerational expansions. Some polymorphic variants of MMR genes have also been associated with reduced somatic expansions. Since expansionbiased somatic mosaicism likely contributes to disease manifestations, these results suggest that genetic modifiers of instability may also affect disease severity. In this chapter, we provide an overview of the data recently published about DNA instability; the roles of genetic modifiers of trinucleotide repeat dynamics in mouse models; and the possible therapeutic interventions.

show abstract

Progression of basal ganglia pathology in heterozygous Q175 knock‐in Huntington's disease mice

Deng

Wang

Joni

et al. 2020

J of Comparative Neurology

View full text Add to dashboard Cite

We used behavioral testing and morphological methods to detail the progression of basal ganglia neuron type-specific pathology and the deficits stemming from them in male heterozygous Q175 mice, compared to age-matched WT males. A rotarod deficit was not present in Q175 mice until 18 months, but increased open field turn rate (reflecting hyperkinesia) and open field anxiety were evident at 6 months. No loss of striatal neurons was seen out to 18 months, but ENK+ and DARPP32+ striatal perikarya were fewer by 6 months, due to diminished expression, with further decline by 18 months. No reduction in SP+ striatal perikarya or striatal interneurons was seen in Q175 mice at 18 months, but cholinergic interneurons showed dendrite attenuation by 6 months. Despite reduced ENK expression in indirect pathway striatal perikarya, ENK-immunostained terminals in globus pallidus externus (GPe) were more abundant at 6 months and remained so out to 18 months. Similarly, SP-immunostained terminals from striatal direct pathway neurons were more abundant in globus pallidus internus and substantia nigra at 6 months and remained so at 18 months. FoxP2+ arkypallidal GPe neurons and subthalamic nucleus neurons were lost by 18 months but not prototypical PARV+ GPe neurons or dopaminergic nigral neurons. Our results show that striatal projection neuron abnormalities and behavioral abnormalities reflecting them develop between 2 and 6 months of age in Q175 male heterozygotes, indicating early effects of the HD mutation. The striatal pathologies resemble those in human HD, but are less severe at 18 months than even in premanifest HD.

show abstract

CAG repeat lengths ≥ 335 attenuate the phenotype in the R6/2 Huntington's disease transgenic mouse

Cited by 69 publications

References 119 publications

Translation of HTT mRNA with expanded CAG repeats is regulated by the MID1–PP2A protein complex

Translation of HTT mRNA with expanded CAG repeats is regulated by the MID1–PP2A protein complex

Genetic Modifiers of CAG.CTG Repeat Instability in Huntington's Disease Mouse Models

Progression of basal ganglia pathology in heterozygous Q175 knock‐in Huntington's disease mice

Contact Info

Product

Resources

About