Abstract
Huntington disease (HD) is caused by an expansion of the polyglutamine (polyQ) repeat (>37Q) in huntingtin (htt), and age of onset is inversely correlated with the length of the polyQ repeat. Mutant htt with expanded polyQ is ubiquitously expressed in various types of cells, including glia, but causes selective neurodegeneration. Our recent study demonstrated that expression of the N-terminal mutant htt with a large polyQ repeat (160Q) in astrocytes is sufficient to induce neurological symptoms in mice (Bradford, J., Shin, J. Y., Roberts, M., Wang, C. E., Li, X.-J., and Li, S. H. (2009) Proc. Natl. Acad. Sci. U.S.A. 106, 22480-22485). Because glia-neuron interactions are critical for maintaining the normal function and survival of neurons in the brain and because mutant htt is more abundant in neurons than in glial cells, it is important to investigate whether glial htt can still contribute to HD pathology when mutant htt is abundantly expressed in neuronal cells. We generated transgenic mice that express mutant htt with 98Q in astrocytes. Unlike our recently generated htt-160Q transgenic mice, htt-98Q mice do not show obvious neurological phenotypes, suggesting that the length of the polyQ repeat determines the severity of glial dysfunction. However, htt-98Q mice show increased susceptibility to glutamate-induced seizure. Mice expressing mutant htt in astrocytes were mated with N171-82Q mice that express mutant htt primarily in neuronal cells. Double transgenic mice expressing mutant htt in both neuronal and glial cells display more severe neurological symptoms and earlier death than N171-82Q mice. These findings indicate a role of glial mutant htt in exacerbating HD neuropathology and underscore the importance of improving glial function in treating HD.
Highlights
Tously expressed in the body and brain, cause selective neurodegeneration in distinct brain regions in each disease [1]
Mice—We previously found that mutant htt is expressed in glial cells in Huntington disease (HD) mouse brains and that fewer glial cells than neurons display nuclear htt aggregates [12, 16]
Because HD is a late-onset neurological disorder showing age-dependent neuropathology, we wanted to investigate whether the accumulation of mutant htt in glial cells is age-dependent and correlates with disease progression
Summary
Antibodies and Plasmids—Rabbit polyclonal antibody (EM48) and mouse monoclonal antibodies (mEM48) against the N-terminal region (amino acids 1–256) of human htt were described in our previous study [17]. The cDNAs encoding N-terminal human htt (208 amino acids) containing the polyQ repeats were subcloned into the eukaryotic expression vector pGfa at the BamHI restriction site. This vector uses the 2.2-kb fragment of astrocyte-specific human glial fibrillary acidic protein (GFAP) promoter [18]. Using this vector encoding mutant N-terminal (1–208 amino acids) htt with 98Q, we generated htt-98Q transgenic mice. RT-PCR of mouse brain htt and production of glyceraldehyde3-phosphate dehydrogenase (GAPDH) primers have been previously described by our laboratory [5]. A probability level of p Ͻ 0.05 was considered to be statistically significant for all statistical tests
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