Alzheimer's brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication

Proceedings of the National Academy of Sciences of the United States of America - Tập 101 Số 29 - Trang 10726-10731 - 2004
Pınar Coşkun1, M. Flint Beal1, Douglas C. Wallace1
1Center for Molecular and Mitochondrial Medicine and Genetics, University of California, Irvine, CA 92697-3940; and Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10021

Tóm tắt

Defects in mitochondrial oxidative phosphorylation have frequently been associated with Alzheimer's disease (AD), and both inherited and somatic mtDNA mutations have been reported in certain AD cases. To determine whether mtDNA mutations contribute more generally to the etiology of AD, we have investigated the sequence of the mtDNA control region (CR) from AD brains for possible disease-causing mutations. Sixty-five percent of the AD brains harbored the T414G mutation, whereas this mutation was absent from all controls. Moreover, cloning and sequencing of the mtDNA CR from patient and control brains revealed that all AD brains had an average 63% increase in heteroplasmic mtDNA CR mutations and that AD brains from patients 80 years and older had a 130% increase in heteroplasmic CR mutations. In addition, these mutations preferentially altered known mtDNA regulatory elements. Certain AD brains harbored the disease-specific CR mutations T414C and T477C, and several AD brains between 74 and 83 years of age harbored the CR mutations T477C, T146C, and T195C, at levels up to 70–80% heteroplasmy. AD patient brains also had an average 50% reduction in the mtDNA L-strand ND6 transcript and in the mtDNA/nuclear DNA ratio. Because reduced ND6 mRNA and mtDNA copy numbers would reduce brain oxidative phosphorylation, these CR mutations could account for some of the mitochondrial defects observed in AD.

Từ khóa


Tài liệu tham khảo

10.1097/00019052-200008000-00003

10.1016/S0891-5849(02)01021-3

10.1002/jnr.10389

10.1111/j.1749-6632.2002.tb02109.x

10.1046/j.1365-2990.2002.00414.x

10.1016/S0197-4580(01)00314-1

10.1046/j.1471-4159.1994.63062179.x

10.1016/S0197-4580(03)00033-2

10.1016/j.nbd.2003.09.011

10.1046/j.1471-4159.1999.0720700.x

10.1006/exnr.2000.7385

10.1007/s004010050997

10.1523/JNEUROSCI.21-13-04923.2001

10.1016/S0006-2952(01)00919-4

Gibson, G. E. & Huang, H. M. (2002) Front. Biosci. 7, d1007-d1015.11897553

10.1073/pnas.0630589100

10.1006/geno.1994.1525

10.1006/geno.1993.1299

10.1002/(SICI)1096-8628(19960122)61:3<283::AID-AJMG15>3.0.CO;2-P

10.1073/pnas.92.15.6892

10.1136/jmg.33.12.1002

10.1111/j.1365-2990.1997.tb01301.x

10.1016/0304-3940(95)12146-3

10.1002/(SICI)1096-8628(19990702)85:1<20::AID-AJMG6>3.0.CO;2-K

10.1086/373937

10.1126/science.1088434

10.1146/annurev.biochem.66.1.409

10.1126/science.286.5440.774

10.1093/nar/28.21.4350

10.1073/pnas.061013598

10.1073/pnas.242719399

10.1086/318204

10.1093/hmg/11.2.133

10.1006/geno.2001.6515

10.1016/S0002-9297(07)62954-1

10.1038/sj.ejhg.5200629

10.1093/emboj/17.16.4848

10.1093/hmg/ddh071

10.1016/S0169-328X(96)00191-X

10.1007/BF03033167

10.1093/nar/27.11.2434

10.1111/j.1749-6632.2002.tb02113.x

10.1093/nar/28.10.2164

10.1111/j.1749-6632.1996.tb34413.x

10.1016/S0169-328X(00)00268-0

10.1006/nbdi.1999.0273

10.1038/ng0996-55

10.1021/bi990438f

10.1126/science.1091230

Thông tin
Thông tin xuất bản

Proceedings of the National Academy of Sciences of the United States of America

Tập 101 Số 29

10726-10731

Thông tin tác giả