ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2009
Striatal expression of a calmodulin fragment improved motor function, weight loss, and neuropathology in the R6/2 mouse model of Huntington's disease.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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27 citing papers in PubMed, 40 citations in OpenAlex.
- Mice carrying the human dopamine D2 receptor pathogenic mutation p.Met374Arg exhibit hyperactivity and aberrant D2 receptor function.Molecular pharmacology · 2025Article
- Effects of local reduction of endogenous α-synuclein using antisense oligonucleotides on the fibril-induced propagation of pathology through the neural network in wild-type mice.Acta neuropathologica communications · 2024Article
- Binding by calmodulin is coupled to transient unfolding of the third FF domain of Prp40A.Protein science : a publication of the Protein Society · 2023Article
- Gait Abnormalities and Aberrant D2 Receptor Expression and Signaling in Mice Carrying the Human Pathogenic MutationMolecular pharmacology · 2023Article
- Small-Molecule Disruptors of Mutant Huntingtin-Calmodulin Protein-Protein Interaction Attenuate Deleterious Effects of Mutant Huntingtin.ACS chemical neuroscience · 2022Article
- Neuroscience and actometry: An example of the benefits of the precise measurement of behavior.Brain research bulletin · 2022Review
- Mutant Huntingtin Protein Interaction Map Implicates Dysregulation of Multiple Cellular Pathways in Neurodegeneration of Huntington's Disease.Journal of Huntington's disease · 2022Article
- Review
- Discovery of sultam-containing small-molecule disruptors of the huntingtin-calmodulin protein-protein interaction.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2020Article
- Rapid and robust patterns of spontaneous locomotor deficits in mouse models of Huntington's disease.PloS one · 2020Article
- Impaired Cerebellar Development in Mice Overexpressing VGF.Neurochemical research · 2019Article
- Behavioral abnormalities with disruption of brain structure in mice overexpressing VGF.Scientific reports · 2017Article
- Use of a force-sensing automated open field apparatus in a longitudinal study of multiple behavioral deficits in CAG140 Huntington's disease model mice.Behavioural brain research · 2015Article
- ZBTB20 regulates nociception and pain sensation by modulating TRP channel expression in nociceptive sensory neurons.Nature communications · 2014Article
- Striatal synaptosomes from Hdh140Q/140Q knock-in mice have altered protein levels, novel sites of methionine oxidation, and excess glutamate release after stimulation.Journal of Huntington's disease · 2013Article
- Striatal pre-enkephalin overexpression improves Huntington's disease symptoms in the R6/2 mouse model of Huntington's disease.PloS one · 2013Article
- Extracts of adipose derived stem cells slows progression in the R6/2 model of Huntington's disease.PloS one · 2013Article
- Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice.Science (New York, N.Y.) · 2012Article
- Synthetic zinc finger repressors reduce mutant huntingtin expression in the brain of R6/2 mice.Proceedings of the National Academy of Sciences of the United States of America · 2012Article
- Mouse models of polyglutamine diseases in therapeutic approaches: review and data table. Part II.Molecular neurobiology · 2012Review
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder, caused by a polyglutamine expansion in the huntingtin protein (htt). Increasing evidence suggests that transglutaminase (TGase) plays a critical role in the pathophysiology of HD possibly by stabilizing monomeric, polymeric and aggregated htt. We previously reported that in HEK293 and SH-SY5Y cells expression of a calmodulin (CaM)-fragment, consisting of amino acids 76-121 of CaM, decreased binding of CaM to mutant htt, TGase-modified htt and cytotoxicity associated with mutant htt and normalized intracellular calcium release. In this study, an adeno-associated virus (AAV) that expresses the CaM-fragment was injected into the striatum of HD transgenic R6/2 mice. The CaM-fragment significantly reduced body weight loss and improved motor function as indicated by improved rotarod performance, longer stride length, lower stride frequency, fewer low mobility bouts and longer travel distance than HD controls. A small but insignificant increase in survival was observed in R6/2 mice with CaM-fragment expression. Immunoprecipitation studies show that expression of the CaM-fragment reduced TGase-modified htt in the striatum of R6/2 mice. The percentage of htt-positive nuclei and the size of intranuclear htt aggregates were reduced by the CaM-fragment without striatal volume changes. The effects of CaM-fragment appear to be selective, as activity of another CaM-dependent enzyme, CaM-dependent kinase II, was not altered. Moreover, inhibition of TGase-modified htt was substrate-specific since overall TGase activity in the striatum was not altered by treatment with the CaM-fragment. Together, these results suggest that disrupting CaM-htt interaction may provide a new therapeutic strategy for HD.
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