TY - JOUR
T1 - Behavioural abnormalities and selective neuronal loss in HD transgenic mice expressing mutated full-length HD cDNA
AU - Hemachandra Reddy, P.
AU - Williams, Maya
AU - Charles, Vinod
AU - Garrett, Lisa
AU - Pike-Buchanan, Lisa
AU - Whetsell, William O.
AU - Miller, Georgina
AU - Tagle, Danilo A.
N1 - Funding Information:
We thank R. Albin for stimulating discussions and G. Auburger and F.S. Collins for critical reading of the manuscript. We are grateful to M. MacDonald, Y.-F. Liu and R. Myers for generous gifts of HF1, 437 and a HD1 antibodies, respectively. We thank M. Erdos, T. Hernandez, A. Chen, C. Rivas, E. Stockburger and T. Moss for technical assistance. This work was supported in part by USPHS grant NS-28236 to W.O.W.
PY - 1998
Y1 - 1998
N2 - Huntington disease (HD) is an adult-onset, autosomal dominant inherited human neurodegenerative disorder characterized by hyperkinetic involuntary movements, including motor restlessness and chorea, slowing of voluntary movements and cognitive impairment. Selective regional neuron loss and gliosis in striatum, cerebral cortex, thalamus, subthalamus and hippocampus1-4 are well recognized as neuropathological correlates for the clinical manifestations of HD. The underlying genetic mutation is the expansion of CAG trinucleotide repeats (coding for polyglutamines) to 36-121 copies in exon 1 of the HD genes5-8. The HD mRNA and protein product (huntingtin) show wide spread distribution9-11, and thus much remains to be under stood about the selective and progressive neurodegeneration in HD. To create an experimental animal model for HD, transgenic mice were generated showing widespread expression of full length human HD cDNA with either 16, 48 or 89 CAG repeats. Only mice with 48 or 89 CAG repeats manifested progressive behavioural and motor dysfunction with neuron loss and gliosis in striatum, cerebral cortex, thalamus and hippocampus. These animals represent clinically relevant models for HD pathogene sis, and may provide insights into the underlying pathophysiological mechanisms of other triplet repeat disorders.
AB - Huntington disease (HD) is an adult-onset, autosomal dominant inherited human neurodegenerative disorder characterized by hyperkinetic involuntary movements, including motor restlessness and chorea, slowing of voluntary movements and cognitive impairment. Selective regional neuron loss and gliosis in striatum, cerebral cortex, thalamus, subthalamus and hippocampus1-4 are well recognized as neuropathological correlates for the clinical manifestations of HD. The underlying genetic mutation is the expansion of CAG trinucleotide repeats (coding for polyglutamines) to 36-121 copies in exon 1 of the HD genes5-8. The HD mRNA and protein product (huntingtin) show wide spread distribution9-11, and thus much remains to be under stood about the selective and progressive neurodegeneration in HD. To create an experimental animal model for HD, transgenic mice were generated showing widespread expression of full length human HD cDNA with either 16, 48 or 89 CAG repeats. Only mice with 48 or 89 CAG repeats manifested progressive behavioural and motor dysfunction with neuron loss and gliosis in striatum, cerebral cortex, thalamus and hippocampus. These animals represent clinically relevant models for HD pathogene sis, and may provide insights into the underlying pathophysiological mechanisms of other triplet repeat disorders.
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U2 - 10.1038/2510
DO - 10.1038/2510
M3 - Article
C2 - 9771716
AN - SCOPUS:17344367977
SN - 1061-4036
VL - 20
SP - 198
EP - 202
JO - Nature genetics
JF - Nature genetics
IS - 2
ER -