Comparison of huntingtin proteolytic fragments in human lymphoblast cell lines and human brain

Toneff, Thomas; Mende‐Mueller, Liane; Wu, Ying; Hwang, Shin-Rong; Bundey, Richard A.; Thompson, Leslie M.; Chesselet, Marie‐Françoise; Hook, Vivian

doi:10.1046/j.1471-4159.2002.00940.x

Cited by 34 publications

(26 citation statements)

References 29 publications

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“…We believe that these products are genuine and not caused by either multiple integrations or integrations of mixed species, including some full-length and some truncated transgenes, for the following reasons. Our findings are compatible with what is seen in both lymphoblastoid cell lines and in brains expressing full-length huntingtin (29,30). We also see similar patterns in independent clonal lines, where the repeat lengths are the same and also appropriate size differences between the bands detected in the lines with 136 repeats, compared with those with 17 repeats.…”

Section: Cre-dependent Transcription Is Impaired In Full-length Hdsupporting

confidence: 90%

Decreased cAMP Response Element-mediated Transcription

Sugars

Brown

Cook

et al. 2004

Journal of Biological Chemistry

130

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Huntington's disease (HD) is one of nine neurodegenerative diseases caused by an expanded polyglutamine (polyQ) tract within the disease protein. To characterize pathways induced early in HD, we have developed stable inducible PC12 cell lines expressing wild-type or mutant forms of huntingtin exon 1 fragments or the full-length huntingtin protein. Three cAMP response element-binding protein (CREB)-binding protein-dependent transcriptional pathways, regulated by cAMP response element (CRE), retinoic acid response element, and nuclear factor B, show abnormalities in our exon 1 cell model. Of these, the CRE pathway shows the earliest disruption and is significantly down-regulated as early as 12 h following mutant htt transgene induction. This pathway is also the only one of the three that is similarly perturbed in our full-length HD model, where it is also down-regulated at an early time point, compatible with observations in HD brains. Reduced CRE-dependent transcription may contribute to polyQ disease pathogenesis because overexpression of transcriptionally active CREB, but not an inactive form of the protein, is able to protect against polyQ-induced cell death and reduce aggregation.Huntington's disease (HD) 1 is a devastating, autosomal dominant, neurodegenerative disorder caused by a CAG trinucleotide repeat expansion within exon 1 of the huntingtin (htt) gene (1). HD is associated with expansions in excess of 35 CAG repeats, which are translated into an abnormally long glutamine tract (polyQ) within htt. This is believed to confer a deleterious gain-of-function onto the protein (2). HD belongs to a family of nine neurodegenerative diseases caused by polyQ expansions, including spinocerebellar ataxia types 1, 2, 3, 6, 7, and 17; spinobulbar muscular atrophy; and dentatorubral pallidoluysian atrophy.PolyQ diseases are characterized by progressive neuronal loss and by the formation of intraneuronal protein aggregates containing the mutant proteins (reviewed in Ref. 3). Although the precise roles of these aggregates in the disease process are still under debate, recent findings have shown them to have a possible pathogenic role in vivo (4). Normally, htt is distributed predominantly within the cytoplasm, although some fulllength htt and N-terminal cleavage fragments are also found in the nucleus (5, 6). For mutant htt, however, nuclear localization is increased, suggesting that transcriptional disruption may be a possible mechanism for polyQ disease pathogenesis (reviewed in Ref. 7).Soluble and aggregated polyQ proteins have been shown to interact/associate with a number of transcription factors and co-factors, which in several cases results in their functional impairment (reviewed in Ref. 7). To date, most attention has fallen on disruption of the transcriptional co-activator protein cAMP response element-binding protein (CBP). CBP facilitates gene transcription under normal conditions by acting as a bridge between specific upstream transcription factors and the basal transcriptional machinery (reviewed in Refs....

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Section: Cre-dependent Transcription Is Impaired In Full-length Hdsupporting

confidence: 90%

Decreased cAMP Response Element-mediated Transcription

Sugars

Brown

Cook

et al. 2004

Journal of Biological Chemistry

130

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“…Calpain and caspase cleavage products have been shown to be present in HD post-mortem tissue (13,20,36). Careful analysis of HD post-mortem tissue shows extensive proteolysis (37). The resulting N-terminal fragments of HTT have been shown to be toxic to neurons in mice and flies.…”

Section: Huntington Disease (Hd)mentioning

confidence: 99%

Integration-independent Transgenic Huntington Disease Fragment Mouse Models Reveal Distinct Phenotypes and Life Span in Vivo

O’Brien

DeGiacomo

Holcomb

et al. 2015

Journal of Biological Chemistry

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Background: Huntington disease is characterized by the generation of mutant huntingtin fragments, which correlate with disease progression. Results: The transgenic mice N171-Q148 and N552-Q148 display a significantly accelerated phenotype and shortened life span when compared with N463-Q148, N536-Q148, and N586-Q148 transgenic mice. Conclusion: Some HTT proteolysis fragments have distinct neurotoxicity. Significance: Reducing proteolysis of huntingtin is a viable therapeutic treatment for Huntington disease.

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“…Furthermore, HTT protein proteolysis has been demonstrated in lymphoblast cell lines from patients with HD (21). To identify HTT fragments in peripheral immune cells, a previously described unbiased immunoprecipitation and immunodetection strategy was used (18).…”

Section: Figurementioning

confidence: 99%