2000/05/23 by Joan S. Steffan, Aleksey Kazantsev, Olivera Spasić-Bošković +7 · 4 citations
Neuroscience · Biochemistry, Genetics and Molecular Biology · #Genetic Neurodegenerative Diseases #Muscle Physiology and Disorders #Mitochondrial Function and Pathology
paper · doi:10.1073/pnas.100110097
openalex publication_date 2000/05/23 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01
Huntington's Disease (HD) is caused by an expansion of a polyglutamine tract within the huntingtin (htt) protein. Pathogenesis in HD appears to include the cytoplasmic cleavage of htt and release of an amino-terminal fragment capable of nuclear localization. We have investigated potential consequences to nuclear function of a pathogenic amino-terminal region of htt (httex1p) including aggregation, protein-protein interactions, and transcription. httex1p was found to coaggregate with p53 in inclusions generated in cell culture and to interact with p53 in vitro and in cell culture. Expanded httex1p represses transcription of the p53-regulated promoters, p21(WAF1/CIP1) and MDR-1. httex1p was also found to interact in vitro with CREB-binding protein (CBP) and mSin3a, and CBP to localize to neuronal intranuclear inclusions in a transgenic mouse model of HD. These results raise the possibility that expanded repeat htt causes aberrant transcriptional regulation through its interaction with cellular transcription factors which may result in neuronal dysfunction and cell death in HD.