Expression of Huntington's disease protein results in apoptotic neurons in the brains of cloned transgenic pigs

• Authors: Dongshan Yang, Chinese Academy of Sciences; Chuan-En Wang, Emory University; Bentian Zhao, Chinese Academy of Sciences; Wei Li, Chinese Academy of Sciences; Zhen Ouyang, Chinese Academy of Sciences; Zhaoming Liu, Chinese Academy of Sciences; Huaqiang Yang, Chinese Academy of Sciences; Pei Fan, Southern Medical University; Ashley O'Neill, Emory University; Weiwang Gu, Southern Medical University; Hong Yi, Emory University; Shihua Li, Emory University; Liangxue Lai, Chinese Academy of Sciences; Xiao-Jiang Li, Emory University
• Journal Title: Human Molecular Genetics
• Volume: Volume 19, Number 20
• Publisher: Oxford University Press | 2010-10-15, Pages 3983-3994
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1093/hmg/ddq313
• Subjects: Biology, Genetics; Biology, Cell

Abstract

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.