ArticleHuman molecular genetics2011
Transgenic mice expressing caspase-6-derived N-terminal fragments of mutant huntingtin develop neurologic abnormalities with predominant cytoplasmic inclusion pathology composed largely of a smaller proteolytic derivative.
Article in Human molecular genetics, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers, 1 of them a synthesis that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
23 citing papers in PubMed, 1 synthesis or guideline pooled it, 41 citations in OpenAlex.
- The proteasome as a druggable target with multiple therapeutic potentialities: Cutting and non-cutting edges.Pharmacology & therapeutics · 2020Pooled it
- Rodent Models of Huntington's Disease: An Overview.Biomedicines · 2023Review
- Cogs in the autophagic machine-equipped to combat dementia-prone neurodegenerative diseases.Frontiers in molecular neuroscience · 2023Review
- Truncation of mutant huntingtin in knock-in mice demonstrates exon1 huntingtin is a key pathogenic form.Nature communications · 2020Article
- Deubiquitinase Usp12 functions noncatalytically to induce autophagy and confer neuroprotection in models of Huntington's disease.Nature communications · 2018Article
- Differential susceptibility of striatal, hippocampal and cortical neurons to Caspase-6.Cell death and differentiation · 2018Article
- Murine Aβ over-production produces diffuse and compact Alzheimer-type amyloid deposits.Acta neuropathologica communications · 2015Article
- Transcriptional dysregulation of inflammatory/immune pathways after active vaccination against Huntington's disease.Human molecular genetics · 2015Article
- Integration-independent Transgenic Huntington Disease Fragment Mouse Models Reveal Distinct Phenotypes and Life Span in Vivo.The Journal of biological chemistry · 2015Article
- A Huntingtin-based peptide inhibitor of caspase-6 provides protection from mutant Huntingtin-induced motor and behavioral deficits.Human molecular genetics · 2015Article
- Choosing an animal model for the study of Huntington's disease.Nature reviews. Neuroscience · 2013Review
- Unbiased screen reveals ubiquilin-1 and -2 highly associated with huntingtin inclusions.Brain research · 2013Article
- Huntington's disease: underlying molecular mechanisms and emerging concepts.Trends in biochemical sciences · 2013Review
- Robust cytoplasmic accumulation of phosphorylated TDP-43 in transgenic models of tauopathy.Acta neuropathologica · 2013Article
- PolyQ disease: misfiring of a developmental cell death program?Trends in cell biology · 2013Review
- Mouse models of polyglutamine diseases in therapeutic approaches: review and data table. Part II.Molecular neurobiology · 2012Review
- Mouse models of polyglutamine diseases: review and data table. Part I.Molecular neurobiology · 2012Review
- Peptide inhibitors: Four of a kind beats a pair.Nature chemical biology · 2012Article
- Identification of novel potentially toxic oligomers formed in vitro from mammalian-derived expanded huntingtin exon-1 protein.The Journal of biological chemistry · 2012Article
- Rescue from excitotoxicity and axonal degeneration accompanied by age-dependent behavioral and neuroanatomical alterations in caspase-6-deficient mice.Human molecular genetics · 2012Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
11 authors at 3 institutions in 2 countries.
Funding
Abstract
Recent studies have implicated an N-terminal caspase-6 cleavage product of mutant huntingtin (htt) as an important mediator of toxicity in Huntington's disease (HD). To directly assess the consequences of such fragments on neurologic function, we produced transgenic mice that express a caspase-6 length N-terminal fragment of mutant htt (N586) with both normal (23Q) and disease (82Q) length glutamine repeats. In contrast to mice expressing N586-23Q, mice expressing N586-82Q accumulate large cytoplasmic inclusion bodies that can be visualized with antibodies to epitopes throughout the N586 protein. However, biochemical analyses of aggregated mutant huntingtin in these mice demonstrated that the inclusion bodies are composed largely of a much smaller htt fragment (terminating before residue 115), with lesser amounts of full-length N586-82Q fragments. Mice expressing the N586-82Q fragment show symptoms typical of previously generated mice expressing mutant huntingtin fragments, including failure to maintain weight, small brain weight and reductions in specific mRNAs in the striatum. Uniquely, these N586-82Q mice develop a progressive movement disorder that includes dramatic deficits in motor performance on the rotarod and ataxia. Our findings suggest that caspase-6-derived fragments of mutant htt are capable of inducing novel HD-related phenotypes, but these fragments are not terminal cleavage products as they are subject to further proteolysis. In this scenario, mutant htt fragments derived from caspase 6, or possibly other proteases, could mediate HD pathogenesis via a 'hit and run' type of mechanism in which caspase-6, or other larger N-terminal fragments, mediate a neurotoxic process before being cleaved to a smaller fragment that accumulates pathologically.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.