期刊
HUMAN MOLECULAR GENETICS
卷 28, 期 3, 页码 487-500出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddy363
关键词
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资金
- Hereditary Disease Foundation
- National Institutes of Health/National Institute of Neurological Disorders and Stroke [NS069614, NS089750-01A1, NS41574, NS96994, U54HD087101]
Neuronal and non-neuronal cells express the huntingtin (HTT) protein, yet neurodegeneration in Huntington's disease (HD) is largely selective, affecting most prominently striatal medium spiny neurons and cortical pyramidal neurons. Selective toxicity of full-length human mutant HTT (fl-mHTT) may be due in part to its expression in non-neuronal cells. While studies suggest neuronal-glial interactions are important in HD and fl-mHTT is expressed in astrocytes, it has not been determined whether the expression of fl-mHTT in astrocytes is necessary for HD pathogenesis. To directly assess the necessity of fl-mHTT in astrocytes for HD pathogenesis, we used a mouse genetic approach and bred the conditional mHTT-expressing BACHD mouse model with GFAP-CreER(T2) mice. We show that GFAP-CreER(T2) expression in these mice is highly selective for astrocytes, and we are able to significantly reduce the expression of fl-mHTT protein in the striatum and cortex of BACHD/GFAP-CreER(T2)-tam mice. We performed behavioral, electrophysiological and neuropathological analyses of BACHD and BACHD/GFAP-CreER(T2)-tam mice. Behavioral analyses of BACHD/GFAP-CreER(T2)-tam mice demonstrate significant improvements in motor and psychiatric-like phenotypes. We observe improvements in neuropathological and electrophysiological phenotypes in BACHD/GFAP-CreER(T2)-tam mice compared to BACHD mice. We observed a restoration of the normal level alpha B-crystallin in the striatum of the BACHD/GFAP-CreER(T2) mice, indicating a cell autonomous effect of mHTT on its expression. Taken together, this work indicates that astrocytes are important contributors to the progression of the behavioral and neuropathological phenotypes observed in HD.
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