Suppression of Somatic Expansion Delays the Onset of Pathophysiology in a Mouse Model of Huntington’s Disease
作者： Helen Budworth , Faye R. Harris , Paul Williams , Do Yup Lee , Amy Holt
DOI: 10.1371/JOURNAL.PGEN.1005267
关键词: Genetics 、 Somatic cell 、 Biology 、 Disease 、 Huntington's disease 、 Toxicity 、 Pathophysiology 、 DNA damage 、 Immunology 、 Allele 、 Trinucleotide repeat expansion
摘要: Huntington’s Disease (HD) is caused by inheritance of a single disease-length allele harboring an expanded CAG repeat, which continues to expand in somatic tissues with age. The inherited disease expresses toxic protein, and whether further expansion adds toxicity unknown. We have created HD mouse model that resolves the effects expansions. show here suppressing substantially delays onset littermates inherit same allele. Furthermore, pharmacological inhibitor, XJB-5-131, inhibits lengthening repeat tracks, correlates rescue motor decline these animals. results provide evidence approaches offset progression are possible.
core.ac.uk
osti.gov
doaj.org参考文章(51)
Kevin Manley, Thomas L. Shirley, Lorraine Flaherty, Anne Messer, Msh2 deficiency prevents in vivo somatic instability of the CAG repeat in Huntington disease transgenic mice. Nature Genetics. ,vol. 23, pp. 471- 473 ,(1999) , 10.1038/70598
Irina V. Kovtun, Cynthia T. McMurray, Trinucleotide expansion in haploid germ cells by gap repair Nature Genetics. ,vol. 27, pp. 407- 411 ,(2001) , 10.1038/86906
J Michael Andresen, Javier Gayán, Luc Djoussé, Simone Roberts, Denise Brocklebank, Stacey S Cherny, US‐Venezuela Collaborative Research Group, HD MAPS Collaborative Research Group, Lon R Cardon, James F Gusella, Marcy E MacDonald, Richard H Myers, David E Housman, Nancy S Wexler, None, The relationship between CAG repeat length and age of onset differs for Huntington's disease patients with juvenile onset or adult onset. Annals of Human Genetics. ,vol. 71, pp. 295- 301 ,(2007) , 10.1111/J.1469-1809.2006.00335.X
Ferdinando Squitieri, Luigi Frati, Estrella Gómez-Tortosa, Carmen Ayuso García, Oksana Suchowersky, Mary Lou Klimek, Ronald JA Trent, Elizabeth McCusker, Andrea Novelletto, Marina Frontali, Jane S Paulsen, Randi Jones, Tetsuo Ashizawa, Alice Lazzarini, Vanessa C Wheeler, Ranjana Prakash, Gang Xu, Luc Djoussé, Jayalakshmi Srinidhi Mysore, Tammy Gillis, Michael Hakky, L Adrienne Cupples, Marie H Saint-Hilaire, Jang-Ho J Cha, Steven M Hersch, John B Penney, Madaline B Harrison, Susan L Perlman, Andrea Zanko, Ruth K Abramson, Anthony J Lechich, Ayana Duckett, Karen Marder, P Michael Conneally, James F Gusella, Marcy E MacDonald, Richard H Myers, Jian-Liang Li, Michael R Hayden, Simon C Warby, Alexandra Durr, Patrick J Morrison, Martha Nance, Christopher A Ross, Russell L Margolis, Adam Rosenblatt, Genome-wide significance for a modifier of age at neurological onset in Huntington's Disease at 6q23-24: the HD MAPS study BMC Medical Genetics. ,vol. 7, pp. 71- 71 ,(2006) , 10.1186/1471-2350-7-71
Marina Kovalenko, Ella Dragileva, Jason St. Claire, Tammy Gillis, Jolene R. Guide, Jaclyn New, Hualing Dong, Raju Kucherlapati, Melanie H. Kucherlapati, Michelle E. Ehrlich, Jong-Min Lee, Vanessa C. Wheeler, Msh2 Acts in Medium-Spiny Striatal Neurons as an Enhancer of CAG Instability and Mutant Huntingtin Phenotypes in Huntington’s Disease Knock-In Mice PLOS ONE. ,vol. 7, pp. 44273- ,(2012) , 10.1371/JOURNAL.PONE.0044273
Tsuyoshi Arai, Vincent P. Kelly, Osamu Minowa, Tetsuo Noda, Susumu Nishimura, The study using wild-type and Ogg1 knockout mice exposed to potassium bromate shows no tumor induction despite an extensive accumulation of 8-hydroxyguanine in kidney DNA. Toxicology. ,vol. 221, pp. 179- 186 ,(2006) , 10.1016/J.TOX.2006.01.004
Niels de Wind, Marleen Dekker, Anton Berns, Miroslav Radman, Hein te Riele, Inactivation of the mouse Msh2 gene results in mismatch repair deficiency, methylation tolerance, hyperrecombination, and predisposition to cancer Cell. ,vol. 82, pp. 321- 330 ,(1995) , 10.1016/0092-8674(95)90319-4
Cynthia T. McMurray, Mechanisms of trinucleotide repeat instability during human development Nature Reviews Genetics. ,vol. 11, pp. 786- 799 ,(2010) , 10.1038/NRG2828
Susan E. Andrew, Y. Paul Goldberg, Berry Kremer, Håkan Telenius, Jane Theilmann, Shelin Adam, Elizabeth Starr, Ferdinando Squitieri, Biaoyang Lin, Michael A. Kalchman, Rona K. Graham, Michael R. Hayden, The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease Nature Genetics. ,vol. 4, pp. 398- 403 ,(1993) , 10.1038/NG0893-398
Pascal Kahlem, Philippe Djian, The expanded CAG repeat associated with juvenile Huntington disease shows a common origin of most or all neurons and glia in human cerebrum Neuroscience Letters. ,vol. 286, pp. 203- 207 ,(2000) , 10.1016/S0304-3940(00)01029-6