Full-Length Human Mutant Huntingtin with a Stable Polyglutamine Repeat Can Elicit Progressive and Selective Neuropathogenesis in BACHD Mice
| Autor: | Véronique M. André, Irene Yamazaki, Michelle Gray, Jifang Tao, Yi E. Sun, Carlos Cepeda, Shihua Li, Xiao-Hong Lu, Xiao-Jiang Li, Dyna I. Shirasaki, Michael Levine, Brian Wilburn, X. William Yang |
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| Rok vydání: | 2008 |
| Předmět: |
Genetically modified mouse
Chromosomes Artificial Bacterial Patch-Clamp Techniques Huntingtin Mice Transgenic Nerve Tissue Proteins Neuropathology Biology Article Membrane Potentials Histones Mice Microscopy Electron Transmission Huntington's disease Huntingtin Protein medicine Animals Humans Neurons Analysis of Variance Behavior Animal General Neuroscience Neurodegeneration Age Factors Brain Nuclear Proteins medicine.disease Disease Models Animal Huntington Disease medicine.anatomical_structure Gene Expression Regulation Mutation Disease Progression Neuropathogenesis Neuron Peptides Neuroscience Subcellular Fractions |
| Zdroj: | Journal of Neuroscience. 28:6182-6195 |
| ISSN: | 1529-2401 0270-6474 |
| Popis: | To elucidate the pathogenic mechanisms in Huntington's disease (HD) elicited by expression of full-length human mutant huntingtin (fl-mhtt), a bacterial artificial chromosome (BAC)-mediated transgenic mouse model (BACHD) was developed expressing fl-mhtt with 97 glutamine repeats under the control of endogenous htt regulatory machinery on the BAC. BACHD mice exhibit progressive motor deficits, neuronal synaptic dysfunction, and late-onset selective neuropathology, which includes significant cortical and striatal atrophy and striatal dark neuron degeneration. Power analyses reveal the robustness of the behavioral and neuropathological phenotypes, suggesting BACHD as a suitable fl-mhtt mouse model for preclinical studies. Additional analyses of BACHD mice provide novel insights into how mhtt may elicit neuropathogenesis. First, unlike previous fl-mhtt mouse models, BACHD mice reveal that the slowly progressive and selective pathogenic process in HD mouse brains can occur without early and diffuse nuclear accumulation of aggregated mhtt (i.e., as detected by immunostaining with the EM48 antibody). Instead, a relatively steady-state level of predominantly full-length mhtt and a small amount of mhtt N-terminal fragments are sufficient to elicit the disease process. Second, the polyglutamine repeat within fl-mhtt in BACHD mice is encoded by a mixed CAA-CAG repeat, which is stable in both the germline and somatic tissues including the cortex and striatum at the onset of neuropathology. Therefore, our results suggest that somatic repeat instability does not play a necessary role in selective neuropathogenesis in BACHD mice. In summary, the BACHD model constitutes a novel and robust in vivo paradigm for the investigation of HD pathogenesis and treatment. |
| Databáze: | OpenAIRE |
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