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
Pinar E CoskunDouglas C Wallace

Abstract

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 ...Continue Reading

References

Jul 18, 1995·Proceedings of the National Academy of Sciences of the United States of America·T Hutchin, G Cortopassi
Sep 15, 1994·Genomics·M Corral-DebrinskiD C Wallace
Dec 1, 1994·Journal of Neurochemistry·E M MutisyaM F Beal
Jan 17, 1996·Annals of the New York Academy of Sciences·A D RosesP T Xi
Jan 22, 1996·American Journal of Medical Genetics·M D BrownD C Wallace
Jan 1, 1997·Annual Review of Biochemistry·G S Shadel, D A Clayton
Aug 1, 1997·Neuropathology and Applied Neurobiology·R EgenspergerM B Graeber
Sep 2, 2000·Current Opinion in Neurology·A TandonP H St George-Hyslop
Oct 18, 2000·American Journal of Human Genetics·M RichardsH J Bandelt
Jan 3, 2001·American Journal of Human Genetics·P F ChinneryD M Turnbull
Feb 13, 2001·Brain Research. Molecular Brain Research·C RamassamyJ Poirier
Mar 29, 2001·Proceedings of the National Academy of Sciences of the United States of America·Y WangG Attardi
Apr 21, 2001·European Journal of Human Genetics : EJHG·B Rodríguez-SantiagoV Nunes
Jan 26, 2002·Human Molecular Genetics·Michael T LinM Flint Beal
Mar 19, 2002·Frontiers in Bioscience : a Journal and Virtual Library·Gary E Gibson, Hsueh-Meei Huang
Apr 27, 2002·Annals of the New York Academy of Sciences·Denham Harman
Apr 27, 2002·Annals of the New York Academy of Sciences·Hilary A CollerKonstantin Khrapko
May 7, 2002·Biochemical Pharmacology·Domenico Praticò
Oct 9, 2002·Neuropathology and Applied Neurobiology·D A CottrellD M Turnbull
Oct 23, 2002·Journal of Neuroscience Research·Rudy CastellaniMark A Smith
Oct 26, 2002·Free Radical Biology & Medicine·Mark A SmithGeorge Perry
Jan 23, 2003·Proceedings of the National Academy of Sciences of the United States of America·Jin ZhangGiuseppe Attardi
Feb 13, 2003·Annals of the New York Academy of Sciences·David G Lavond
Feb 28, 2003·Proceedings of the National Academy of Sciences of the United States of America·Pinar E CoskunDouglas C Wallace
Mar 6, 2003·American Journal of Human Genetics·Joelle M van der WaltJeffery M Vance
Dec 17, 2003·Neurobiology of Aging·Sandra Morais CardosoCatarina R Oliveira
Jan 13, 2004·Science·Eduardo Ruiz-PesiniDouglas C Wallace

❮ Previous
Next ❯

Citations

Feb 6, 2009·Journal of Applied Genetics·K TońskaE Bartnik
Jul 8, 2008·Journal of Neurology·Andreas BenderThomas Klopstock
May 24, 2011·Journal of Neurology·Massimiliano FilostoAlessandro Padovani
Jan 13, 2006·Human Genetics·Joanna L ElsonNeil Howell
Aug 9, 2011·Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology·Dana M ReiffRalph M Garruto
Dec 23, 2006·Cellular and Molecular Neurobiology·Farzaneh FesahatFarzaneh Mirzajani
Oct 3, 2009·Journal of Bioenergetics and Biomembranes·Michelangelo MancusoLuigi Murri
Oct 2, 2009·Journal of Bioenergetics and Biomembranes·Alicia M PickrellCarlos T Moraes
Jun 11, 2005·Clinical Biochemistry·Dongchon Kang, Naotaka Hamasaki
Aug 5, 2005·Nature Medicine·Charlotte Schubert
Aug 8, 2006·Oncogene·M BrandonD C Wallace
Dec 4, 2008·Proceedings of the National Academy of Sciences of the United States of America·Xinglong WangXiongwei Zhu
Aug 6, 2008·The Journal of Biological Chemistry·Lily KhidrWen-Hwa Lee
Aug 24, 2005·Antioxidants & Redox Signaling·Patricia A Trimmer, M Kathleen Borland
Aug 19, 2007·Antioxidants & Redox Signaling·P Hemachandra Reddy
Sep 25, 2007·Antioxidants & Redox Signaling·Michelangelo MancusoGabriele Siciliano
Sep 8, 2007·Antioxidants & Redox Signaling·Jose ViñaMaria-Dolores Alonso
Nov 30, 2011·Antioxidants & Redox Signaling·Rommy von Bernhardi, Jaime Eugenín
Nov 29, 2011·Antioxidants & Redox Signaling·Karen SchmittAnne Eckert
Dec 12, 2012·Antioxidants & Redox Signaling·Renato X SantosGeorge Perry
Sep 8, 2005·Rejuvenation Research·Rafal M Smigrodzki, Shaharyar M Khan
Aug 22, 2007·Rejuvenation Research·P J CrouchI A Trounce
Dec 21, 2004·Nucleic Acids Research·Marty C BrandonDouglas C Wallace
Dec 31, 2005·Nucleic Acids Research·Jochen KohlArndt von Haeseler
Mar 9, 2010·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Christos ChinopoulosVera Adam-Vizi
May 5, 2009·Cornea·Shari R AtilanoM Cristina Kenney
Mar 23, 2012·AIDS·Marissa H J JitratkosolUNKNOWN CIHR Emerging Team Grant on HIV Therapy and Aging (CARMA)
Aug 5, 2009·Genes & Development·Douglas C Wallace, Weiwei Fan
Nov 8, 2007·Respirology : Official Journal of the Asian Pacific Society of Respirology·Massoud HoushmandMehdi S Mirsaeidi
May 10, 2006·Genes, Brain, and Behavior·M GrazinaC Oliveira
Mar 23, 2007·Genes, Brain, and Behavior·H W WienerR C P Go
Jun 16, 2012·The Journal of Pharmacology and Experimental Therapeutics·Ashu Johri, M Flint Beal
Nov 18, 2009·Biochemistry. Biokhimii︠a︡·I N Todorov, G I Todorov
Nov 28, 2007·Annual Review of Pathology·Bruce A YanknerPatrick Loerch
Apr 24, 2012·Journal of Aging Research·Carlos SpuchCarmen Navarro
Apr 2, 2013·The Journal of Clinical Investigation·Douglas C Wallace

❮ Previous
Next ❯

Related Concepts

Related Feeds

Alzheimer's Disease: Transcription

Impaired transcription is associated with the pathogenesis and progression of conditions such as Alzheimer's disease (AD). Here are the latest discoveries pertaining to transcription and AD.