Neuronal targets for reducing mutant huntingtin expression to ameliorate disease in a mouse model of Huntington's disease
| Autor: | Michelle Gray, Carlos Cepeda, Dyna I. Shirasaki, Erin R. Greiner, Jeffrey P. Cantle, Xiao-Hong Lu, Sandra M. Holley, Xiaofeng Gu, Hong-Wei Dong, X. William Yang, Nan Wang, Michael Levine, Yuqing Li |
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| Rok vydání: | 2013 |
| Předmět: |
Genetically modified mouse
Pathology medicine.medical_specialty Huntingtin Transgene Nerve Tissue Proteins Striatum Behavioral Symptoms Biology Motor Activity General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Mice 0302 clinical medicine Huntington's disease medicine Huntingtin Protein Animals Humans 030304 developmental biology Neurons 0303 health sciences Neurodegeneration General Medicine Genetic Therapy medicine.disease Corpus Striatum Disease Models Animal Huntington Disease nervous system Gene Expression Regulation Mutation Trinucleotide repeat expansion Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Nature medicine. 20(5) |
| ISSN: | 1546-170X |
| Popis: | Huntington's disease (HD) is a fatal dominantly inherited neurodegenerative disorder caused by a CAG repeat expansion leading to an elongated polyglutamine stretch in huntingtin. Mutant huntingtin (mHTT) is ubiquitously expressed in all cells but elicits selective cortical and striatal neurodegeneration in HD. The mechanistic basis for such selective neuronal vulnerability remains unclear. A necessary step toward resolving this enigma is to define the cell types in which mHTT expression is causally linked to the disease pathogenesis. Using a conditional transgenic mouse model of HD, in which the mice express full-length human mHTT from a bacterial artificial chromosome transgene (BACHD), we genetically reduced mHTT expression in neuronal populations in the striatum, cortex or both. We show that reduction of cortical mHTT expression in BACHD mice partially improves motor and psychiatric-like behavioral deficits but does not improve neurodegeneration, whereas reduction of mHTT expression in both neuronal populations consistently ameliorates all behavioral deficits and selective brain atrophy in this HD model. Furthermore, whereas reduction of mHTT expression in cortical or striatal neurons partially ameliorates corticostriatal synaptic deficits, further restoration of striatal synaptic function can be achieved by reduction of mHTT expression in both neuronal cell types. Our study demonstrates distinct but interacting roles of cortical and striatal mHTT in HD pathogenesis and suggests that optimal HD therapeutics may require targeting mHTT in both cortical and striatal neurons. |
| Databáze: | OpenAIRE |
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