TY - JOUR
T1 - Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation
AU - Davies, Stephen W.
AU - Turmaine, Mark
AU - Cozens, Barbara A.
AU - DiFiglia, Marian
AU - Sharp, Alan H.
AU - Ross, Christopher A.
AU - Scherzinger, Eberhard
AU - Wanker, Erich E.
AU - Mangiarini, Laura
AU - Bates, Gillian P.
N1 - Funding Information:
We thank Amarbirpal Mahal for genotype analysis, Michel Goedert for generous gifts of antibodies to tau and β-amyloid, Gerrard Evan and David Hancock for antibodies to NGFI-A, Fran Ebling for antibodies to Fos B, Steven Hersch for antibodies to htt (HD3.10.6), John Parnavelas for expert advice on electron microscopy, and Adrienne Knight for proof reading the manuscript. This work was supported by the Medical Research Council, the Wellcome Trust (M/96/262), the Hereditary Disease Foundation (in the form of an award donated by Harry Liebermann), the Special Trustees of Guy's and St. Thomas' Hospitals, the European Union, and the Deutsche Forschungsgemeinschaft.
PY - 1997/8/8
Y1 - 1997/8/8
N2 - Huntington's disease (HD) is one of an increasing number of human neurodegenerative disorders caused by a CAG/polyglutamine-repeat expansion. The mutation occurs in a gene of unknown function that is expressed in a wide range of tissues. The molecular mechanism responsible for the delayed onset, selective pattern of neuropathology, and cell death observed in HD has not been described. We have observed that mice transgenic for exon 1 of the human HD gene carrying (CAG)115 to (CAG)156 repeat expansions develop pronounced neuronal intranuclear inclusions, containing the proteins huntingtin and ubiquitin, prior to developing a neurological phenotype. The appearance in transgenic mice of these inclusions, followed by characteristic morphological change within neuronal nuclei, is strikingly similar to nuclear abnormalities observed in biopsy material from HD patients.
AB - Huntington's disease (HD) is one of an increasing number of human neurodegenerative disorders caused by a CAG/polyglutamine-repeat expansion. The mutation occurs in a gene of unknown function that is expressed in a wide range of tissues. The molecular mechanism responsible for the delayed onset, selective pattern of neuropathology, and cell death observed in HD has not been described. We have observed that mice transgenic for exon 1 of the human HD gene carrying (CAG)115 to (CAG)156 repeat expansions develop pronounced neuronal intranuclear inclusions, containing the proteins huntingtin and ubiquitin, prior to developing a neurological phenotype. The appearance in transgenic mice of these inclusions, followed by characteristic morphological change within neuronal nuclei, is strikingly similar to nuclear abnormalities observed in biopsy material from HD patients.
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U2 - 10.1016/S0092-8674(00)80513-9
DO - 10.1016/S0092-8674(00)80513-9
M3 - Article
C2 - 9267033
AN - SCOPUS:18544410106
SN - 0092-8674
VL - 90
SP - 537
EP - 548
JO - Cell
JF - Cell
IS - 3
ER -