Alzheimer’s brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication
Pinar E. Coskun *, M. Flint Beal and Douglas C. Wallace *,
*Center 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
Contributed by Douglas C. Wallace, May 24, 2004
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 mtDNACR 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 andT477C, 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 marinade mtDNA copy numbers would reduce brain oxidative phosphorylation,these CR mutations could account for some of the mitochondrial defects observed in AD.
Abbreviations: AD, alzheimer’s disease ; APP, A precursor protein;CR, control region; CSB, conserved sequence block; mtPTP, mitochondrial permeability transition pore; mtTFA, mitochondrial transcription factor A; np, nucleotide pair; OXPHOS, oxidative phosphorylation;PL and PH, L- and H-strand promoters; PNA, protein nucleic acid;ROS, reactive oxygen species.