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匹配条件: “ Vanessa C. Wheeler” ,找到相关结果约222329条。
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Quantification of Age-Dependent Somatic CAG Repeat Instability in Hdh CAG Knock-In Mice Reveals Different Expansion Dynamics in Striatum and Liver
Jong-Min Lee, Ricardo Mouro Pinto, Tammy Gillis, Jason C. St. Claire, Vanessa C. Wheeler
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0023647
Abstract: Background Age at onset of Huntington's disease (HD) is largely determined by the CAG trinucleotide repeat length in the HTT gene. Importantly, the CAG repeat undergoes tissue-specific somatic instability, prevalent in brain regions that are disease targets, suggesting a potential role for somatic CAG repeat instability in modifying HD pathogenesis. Thus, understanding underlying mechanisms of somatic CAG repeat instability may lead to discoveries of novel therapeutics for HD. Investigation of the dynamics of the CAG repeat size changes over time may provide insights into the mechanisms underlying CAG repeat instability. Methodology/Principal Findings To understand how the HTT CAG repeat length changes over time, we quantified somatic instability of the CAG repeat in Huntington's disease CAG knock-in mice from 2–16 months of age in liver, striatum, spleen and tail. The HTT CAG repeat in spleen and tail was very stable, but that in liver and striatum expanded over time at an average rate of one CAG per month. Interestingly, the patterns of repeat instability were different between liver and striatum. Unstable CAG repeats in liver repeatedly gained similar sizes of additional CAG repeats (approximately two CAGs per month), maintaining a distinct population of unstable repeats. In contrast, unstable CAG repeats in striatum gained additional repeats with different sizes resulting in broadly distributed unstable CAG repeats. Expanded CAG repeats in the liver were highly enriched in polyploid hepatocytes, suggesting that the pattern of liver instability may reflect the restriction of the unstable repeats to a unique cell type. Conclusions/Significance Our results are consistent with repeat expansion occurring as a consequence of recurrent small repeat insertions that differ in different tissues. Investigation of the specific mechanisms that underlie liver and striatal instability will contribute to our understanding of the relationship between instability and disease and the means to intervene in this process.
Stoichiometry of Base Excision Repair Proteins Correlates with Increased Somatic CAG Instability in Striatum over Cerebellum in Huntington's Disease Transgenic Mice
Agathi-Vassiliki Goula,Brian R. Berquist,David M. Wilson III,Vanessa C. Wheeler,Yvon Trottier ,Karine Merienne
PLOS Genetics , 2009, DOI: 10.1371/journal.pgen.1000749
Abstract: Huntington's disease (HD) is a progressive neurodegenerative disorder caused by expansion of an unstable CAG repeat in the coding sequence of the Huntingtin (HTT) gene. Instability affects both germline and somatic cells. Somatic instability increases with age and is tissue-specific. In particular, the CAG repeat sequence in the striatum, the brain region that preferentially degenerates in HD, is highly unstable, whereas it is rather stable in the disease-spared cerebellum. The mechanisms underlying the age-dependence and tissue-specificity of somatic CAG instability remain obscure. Recent studies have suggested that DNA oxidation and OGG1, a glycosylase involved in the repair of 8-oxoguanine lesions, contribute to this process. We show that in HD mice oxidative DNA damage abnormally accumulates at CAG repeats in a length-dependent, but age- and tissue-independent manner, indicating that oxidative DNA damage alone is not sufficient to trigger somatic instability. Protein levels and activities of major base excision repair (BER) enzymes were compared between striatum and cerebellum of HD mice. Strikingly, 5′-flap endonuclease activity was much lower in the striatum than in the cerebellum of HD mice. Accordingly, Flap Endonuclease-1 (FEN1), the main enzyme responsible for 5′-flap endonuclease activity, and the BER cofactor HMGB1, both of which participate in long-patch BER (LP–BER), were also significantly lower in the striatum compared to the cerebellum. Finally, chromatin immunoprecipitation experiments revealed that POLβ was specifically enriched at CAG expansions in the striatum, but not in the cerebellum of HD mice. These in vivo data fit a model in which POLβ strand displacement activity during LP–BER promotes the formation of stable 5′-flap structures at CAG repeats representing pre-expanded intermediate structures, which are not efficiently removed when FEN1 activity is constitutively low. We propose that the stoichiometry of BER enzymes is one critical factor underlying the tissue selectivity of somatic CAG expansion.
Supplementary Studies on Ant Larvae: Cerapachyinae,Pseudomyrmecinae and Myrmicinae
George C. Wheeler,Jeanette Wheeler
Psyche , 1973, DOI: 10.1155/1973/67836
Abstract:
The Ant Larvae of the Myrmicine Tribe Myrmicini
George C. Wheeler,Jeanette Wheeler
Psyche , 1952, DOI: 10.1155/1952/76573
Abstract:
The Ant Larvae of the Myrmicine TribesBasicerotini and Dacetini
George C. Wheeler,Jeantte Wheeler
Psyche , 1954, DOI: 10.1155/1954/49606
Abstract:
Young Larvae of Veromessor Pergandei(Hymenoptera: Formicidae: Myrmicinae)
George C. Wheeler,Jeanette Wheeler
Psyche , 1987, DOI: 10.1155/1987/94737
Abstract:
Ant Larvae of Four Tribes: Second Supplement (Hymenoptera:Formicidae: Myrmicinae)
George C. Wheeler,Jeanette Wheeler
Psyche , 1973, DOI: 10.1155/1973/93969
Abstract:
Veromessor Lobognathus in North Dakota (Hymenoptera: Formicidae)
George C. Wheeler,Jeanette Wheeler
Psyche , 1956, DOI: 10.1155/1956/67431
Abstract:
The Ant Larvae of the SubfamilyLeptanillinae (Hymenoptera, Formicidae)
George C. Wheeler,Jeanette Wheeler
Psyche , 1965, DOI: 10.1155/1965/28458
Abstract:
The Larva of Dinoponera (Hymenoptera: Formicidae: Ponerinae)
George C. Wheeler,Jeanette Wheeler
Psyche , 1985, DOI: 10.1155/1985/38707
Abstract:
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