Expression of Huntington's disease protein results in apoptotic neurons in the brains of cloned transgenic pigs.
Neurodegeneration is a hallmark of many neurological diseases, including Alzheimer's, Parkinson's and the polyglutamine diseases, which are all caused by misfolded proteins that accumulate in neuronal cells of the brain. Although apoptosis is believed to contribute to neurodegeneration in these cases, genetic mouse models of these diseases often fail to replicate apoptosis and overt neurodegeneration in the brain. Using nuclear transfer, we generated transgenic Huntington's disease (HD) pigs that express N-terminal (208 amino acids) mutant huntingtin with an expanded polyglutamine tract (105Q). Postnatal death, dyskinesia and chorea-like movement were observed in some transgenic pigs that express mutant huntingtin. Importantly, the transgenic HD pigs, unlike mice expressing the same transgene, displayed typical apoptotic neurons with DNA fragmentation in their brains. Also, expression of mutant huntingtin resulted in more neurons with activated caspase-3 in transgenic pig brains than that in transgenic mouse brains. Our findings suggest that species differences determine neuropathology and underscore the importance of large mammalian animals for modeling neurological disorders.
Yang
Dongshan
D
Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
Wang
Chuan-En
CE
Zhao
Bentian
B
Li
Wei
W
Ouyang
Zhen
Z
Liu
Zhaoming
Z
Yang
Huaqiang
H
Fan
Pei
P
O'Neill
Ashley
A
Gu
Weiwang
W
Yi
Hong
H
Li
Shihua
S
Lai
Liangxue
L
Li
Xiao-Jiang
XJ
D000818:Animals; D030801:Animals, Genetically Modified / Q000378:metabolism; D017209:Apoptosis; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D053148:Caspase 3 / Q000096:biosynthesis; D053938:DNA Fragmentation; D004195:Disease Models, Animal; D015870:Gene Expression; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D019636:Neurodegenerative Diseases; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D057165:Proteostasis Deficiencies; D013045:Species Specificity; D013552:Swine / Q000235:genetics / Q000378:metabolism; D013556:Swine, Miniature / Q000235:genetics / Q000378:metabolism
C086055:HTT protein, human; D000071058:Huntingtin Protein; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D053148:Caspase 3