Skip to main content

Advertisement

SpringerLink
Log in

Does the mitochondrial genome play a role in the etiology of Alzheimer’s disease?

  • Original Investigation
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

We report here the analyses of complete mtDNA coding region sequences from more than 270 Alzheimer’s disease (AD) patients and normal controls to determine if inherited mtDNA mutations contribute to the etiology of AD. The AD patients and normal individuals were carefully screened and drawn from two populations of European descent in an effort to avoid spurious effects due to local population anomalies. Overall, there were no significant haplogroup associations in the combined AD and normal control sequence sets. Reduced median network analysis revealed that the AD mtDNA sequences contained a higher number of substitutions in tRNA genes, and that there was an elevated frequency of replacement substitutions in the complex I genes of the control sequences. Analysis of the replacement substitutions indicated that those arising in the AD mtDNAs were no more deleterious, on average, than those in the control mtDNAs. The only evidence for the synergistic action of mutations was the presence of both a rare non-conservative replacement substitution and a tRNA mutation in 2 AD mtDNAs, from a total of 145, whereas such a combination of mutations was not observed in the control sequences. Overall, the results reported here indicate that pathogenic inherited mtDNA mutations do not constitute a major etiological factor in sporadic AD. At most, a small proportion of AD patients carry a pathogenic mtDNA mutation and a small proportion of cognitively normal aged individuals carry a mtDNA mutation that reduces the risk of AD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Anandatheerthavarada HK, Biswas G, Robin M-A, Avadhani NG (2003) Mitochondrial targeting and a novel transmembrane arrest of Alzheimer’s amyloid precursor protein impairs mitochondrial function in neuronal cells. J Cell Biol 161:41–54

    Article  PubMed  CAS  Google Scholar 

  • Andrews RM, Kubacka I, Chinnery PF, Lightowlers RN, Turnbull DM, Howell N (1999) Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA. Nat Genet 23:147

    Article  PubMed  CAS  Google Scholar 

  • Bandelt H-J, Forster P, Sykes BC, Richards MB (1995) Mitochondrial portraits of human populations using median networks. Genetics 141:743–753

    PubMed  CAS  Google Scholar 

  • Beal MF (2005) Mitochondria take center stage in aging and neurodegeneration. Ann Neurol 58:495–505

    Article  PubMed  CAS  Google Scholar 

  • Bosetti F, Brizzi F, Barogi S, Mancuso M, Siciliano G, Tendi EA, Murri L, Rapoport SI, Solaini G (2002) Cytochrome c oxidase and mitochondrial F1F0-ATPase (ATPase) activities in platelets and brain from patients with Alzheimer’s disease. Neurobiol Aging 23:371–376

    Article  PubMed  CAS  Google Scholar 

  • Brown MD, Yang C-C, Trounce I, Torroni A, Lott MT, Wallace DC (1992) A mitochondrial DNA variant, identified in Leber hereditary optic neuropathy patients, which extends the amino acid sequence of cytochrome c oxidase subunit I. Am J Hum Genet 51:378–385

    PubMed  CAS  Google Scholar 

  • Busciglio J, Pelsman A, Wong C, Pigino G, Yuan M, Mori H, Yankner BA (2002) Altered metabolism of the amyloid β precursor protein is associated with mitochondrial dysfunction in Down’s syndrome. Neuron 33:677–688

    Article  PubMed  CAS  Google Scholar 

  • Cardoso SM, Proenca MT, Santos S, Santana I, Oliveira CR (2004) Cytochrome c oxidase is decreased in Alzheimer’s disease platelets. Neurobiol Aging 25:105–110

    Article  PubMed  CAS  Google Scholar 

  • Casley CS, Land JM, Sharpe MA, Clark JB, Duchen MR, Canevari L (2002) β amyloid fragment 25–35 causes mitochondrial dysfunction in primary cortical neurons. Neurobiol Dis 10:258–267

    Article  PubMed  CAS  Google Scholar 

  • Castellani R, Hirai K, Aliev G, Drew KL, Nunomura A, Takeda A, Cash AD, Obrenovich ME, Perry G, Smith MA (2002) Role of mitochondrial dysfunction in Alzheimer’s disease. J Neurosci Res 70:357–360

    Article  PubMed  CAS  Google Scholar 

  • Chagnon P, Betard C, Robitaille Y, Cholette A, Gauvreau D (1995) Distribution of cytochrome oxidase activity in various neurodegenerative diseases. Mol Neurosci 6:711–715

    CAS  Google Scholar 

  • Chagnon P, Gee M, Filion M, Robitaille Y, Belouchi M, Gauvreau D (1999) Phylogenetic analyses of the mitochondrial genome indicates significant differences between patients with Alzheimer disease and controls in a French–Canadian founder population. Am J Med Genet 85:20–30

    Article  PubMed  CAS  Google Scholar 

  • Chinnery PF, Johnson M, Taylor RW, Lightowlers RN, Turnbull DM (1997) A novel mitochondrial tRNA phenylalanine gene mutation presenting with acute rhabdomyolysis. Ann Neurol 41:408–410

    Article  PubMed  CAS  Google Scholar 

  • Chinnery PF, Taylor GA, Howell N, Andrews RM, Morris CM, Taylor RW, McKeith IG, Perry RH, Edwardson JA, Turnbull DM (2000) Mitochondrial DNA haplogroups and susceptibility to AD and dementia with Lewy bodies. Neurol 55:302–304

    CAS  Google Scholar 

  • Chinnery PF, Taylor GA, Howell N, Brown DT, Parsons TJ, Turnbull DM (2001) Point mutations of the mtDNA control region in normal and neurodegenerative human brains. Am J Hum Genet 68:529–532

    Article  PubMed  CAS  Google Scholar 

  • Coskun PE, Beal MF, Wallace DC (2004) Alzheimer’s brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication. Proc Natl Acad Sci USA 101:10726–10731

    Article  PubMed  CAS  Google Scholar 

  • Cottrell DA, Blakely EL, Johnson MA, Ince PG, Turnbull DM (2001) Mitochondrial enzyme-deficient hippocampal neurons and choroidal cells in AD. Neurology 57:260–264

    PubMed  CAS  Google Scholar 

  • Cottrell DA, Borthwick GM, Johnson MA, Ince PG, Turnbull DM (2002) The role of cytochrome c oxidase deficient hippocampal neurons in Alzheimer’s disease. J Neuropath Appl Neurobiol 28:390–396

    Article  CAS  Google Scholar 

  • Crouch PJ, Blake R, Duce JA, Ciccotosto GD, Li Q-X, Barnham KJ, Curtain CC, Cherny RA, Cappai R, Dyrks T, Masters CL, Trounce IA (2005) Copper-dependent inhibition of human cytochrome c oxidase by a dimeric conformer of amyloid-β1–42. J Neurosci 25:672–679

    Article  PubMed  CAS  Google Scholar 

  • Danielson SR, Carelli V, Tan G, Martinuzzi A, Schapira AHV, Savontaus M-L, Cortopassi GA (2005) Isolation of transcriptomal changes attributable to LHON mutations and the cybridization process. Brain 128:1026–1037

    Article  PubMed  Google Scholar 

  • DiMauro S, Schon E (2001) Mitochondrial DNA mutations in human disease, Am J Med Genet 106:18–26

    Article  PubMed  CAS  Google Scholar 

  • Elson JL, Turnbull DM, Howell N (2004) Comparative genomics and the evolution of human mitochondrial DNA: assessing the effects of selection. Am J Hum Genet 74:229–238

    Article  PubMed  CAS  Google Scholar 

  • Ghosh SS, Swerdlow RH, Miller SW, Sheeman B, Parker WD, Davis RE (1999) Use of cytoplasmic hybrid lines for elucidating the role of mitochondrial dysfunction in Alzheimer’ disease and Parkinson’s disease. Ann NY Acad Sci 893:176–191

    Article  PubMed  CAS  Google Scholar 

  • Gonnet GH, Cohen MA, Benner SA (1992) Exhaustive matching of the entire protein sequence database. Science 256:1443–1445

    Article  PubMed  CAS  Google Scholar 

  • Herrnstadt C, Howell N (2004) An evolutionary perspective on pathogenic mtDNA mutations: haplogroup associations of clinical disorders. Mitochondrion 4:791–798

    Article  PubMed  CAS  Google Scholar 

  • Herrnstadt C, Elson JL, Fahy E, Preston G, Turnbull DM, Anderson C, Ghosh SS, Olefsky JM, Beal MF, Davis RE, Howell N (2002) Reduced-median-network analysis of complete mitochondrial DNA coding-region sequences for the major African, Asian, and European haplogroups. Am J Hum Genet 70:1152–1171

    Article  PubMed  CAS  Google Scholar 

  • Herrnstadt C, Preston G, Howell N (2003) Errors, phantom and otherwise, in human mtDNA sequences. Am J Hum Genet 72:1585–1586

    Article  PubMed  CAS  Google Scholar 

  • Hirai K, Aliev G, Nunomura A, Fujioka H, Russell RL, Atwood CS, Johnson AB, Kress Y, Vinters HV, Tabaton M, Shimohama S, Cash AD, Siedlak SL, Harris PLR, Jones PK, Petersen RB, Perry G, Smith MA (2001) Mitochondrial abnormalities in Alzheimer’s disease. J Neurosci 21:3017–3023

    PubMed  CAS  Google Scholar 

  • Howell N, Oostra R-J, Bolhuis PA, Spruijt L, Clarke LA, Mackey DA, Preston G, Herrnstadt C (2003a) Sequence analysis of the mitochondrial genomes from Dutch pedigrees with Leber hereditary optic neuropathy. Am J Hum Genet 72:1460–1469

    Article  CAS  Google Scholar 

  • Howell N, Smejkal CB, Mackey DA, Chinnery PF, Turnbull DM, Herrnstadt C (2003b) The pedigree rate of sequence divergence in the human mitochondrial genome: there is a difference between phylogenetic and pedigree rates. Am J Hum Genet 72:659–670

    Article  CAS  Google Scholar 

  • Howell N, Elson JL, Chinnery PF, Turnbull DM (2005) mtDNA mutations and common neurodegenerative disorders. Trends Genet 21:583–584

    Article  PubMed  CAS  Google Scholar 

  • Ioannidis JPA (2005) Why most published research findings are false. PloS Med 2:e124

    Article  PubMed  Google Scholar 

  • Ito S, Ohta S, Nishimaki K, Kagawa Y, Soma R, Kuno S, Komatsuzaki Y, Mizusawa H, Hayashi J-I (1999) Functional integrity of mitochondrial genomes in human platelets and autopsied brain tissues from elderly patients with Alzheimer’s disease. Proc Natl Acad Sci USA 96:2099–2103

    Article  PubMed  CAS  Google Scholar 

  • Keers SM, Gibson AM, Turnbull DM, Chinnery PF (2004) No evidence of an association between the mtDNA 16184-93 polyC tract and late onset dementia. J Med Genet 41:957–958

    Article  Google Scholar 

  • Khan SM, Cassarino DS, Abramova NN, Keeney PM, Borland MK, Trimmer PA, Krebs CT, Bennett JC, Parks JK, Swerdlow RH, Parker WD, Bennett JP (2000) Alzheimer’s disease cybrids replicate β-amyloid abnormalities through cell death pathways. Ann Neurol 48:148–155

    Article  PubMed  CAS  Google Scholar 

  • Kish SJ, Bergeran C, Rajput A, Dozie S, Mastrogiacomo F, Chang LJ, Wilson JM, DiStefano LM, Nobrega JN (1992) Brain cytochrome oxidase activity is reduced in Alzheimer’s disease. J Neurochem 59:776–779

    Article  PubMed  CAS  Google Scholar 

  • Kish SJ, Mastrogiacomo F, Guttman M, Furukawa Y, Taanman J-W, Dozic S, Pandolfo M, Lamarche J, DiStefano L, Chang L-J (1999) Decreased brain protein levels of cytochrome oxidase subunits in Alzheimer’s disease and in hereditary spincerebellar ataxia disorders: a nonspecific change? J Neurochem 72:700–707

    Article  PubMed  CAS  Google Scholar 

  • Kondrashov FA (2005) Prediction of pathogenic mutations in mitochondrially encoded human tRNAs. Hum Mol Genet 14:2415–2419

    Article  PubMed  CAS  Google Scholar 

  • Lehtonen MS, Moilanen JS, Majamaa K (2003) Increased variation in mtDNA in patients with familial sensorineural hearing impairment. Hum Genet 113:220–227

    Article  PubMed  CAS  Google Scholar 

  • Lin MT, Simon DK, Ahn CG, Kim LM, Beal MF (2002) High aggregate burden of somatic mtDNA point mutations in aging and Alzheimer’s disease brain. Hum Mol Genet 11:133–145

    Article  PubMed  CAS  Google Scholar 

  • Maurer I, Zierz S, Moller H-J (2000) A selective defect of cytochrome c oxidase is present in brain of Alzheimer’s disease patients. Neurobiol Aging 21:455–462

    Article  PubMed  CAS  Google Scholar 

  • Mayeux R (2003) Epidemiology of neurodegeneration. Ann Rev Neurosci 26:81–104

    Article  PubMed  CAS  Google Scholar 

  • McFarland R, Elson JL, Taylow RW, Howell N, Turnbull DM (2004a) Assigning pathogenicity to mitochondrial tRNA mutations: when “definitely maybe” is not good enough. Trends Genet 20:591–596

    Article  CAS  Google Scholar 

  • McFarland R, Taylor RW, Chinnery PF, Howell N, Turnbull DM (2004b) A novel sporadic mutation in cytochrome c oxidase subunit II as a cause of rhabdomyolysis. Neuromuscul Disord 14:162–166

    Article  Google Scholar 

  • Moilanen JS, Majamaa K (2003) Phylogenetic network and physiochemical properties of nonsynonymous mutations in the protein-coding genes of human mitochondrial DNA. Mol Biol Evol 20:1195–1210

    Article  PubMed  CAS  Google Scholar 

  • Mutisya EM, Bowling AC, Beal MF (1994) Cortical cytochrome oxidase activity is reduced in Alzheimer’s disease. J Neurochem 63:2179–2184

    Article  PubMed  CAS  Google Scholar 

  • Niemi A-K, Hervonen A, Hurme M, Karhunen PJ, Jylhä M, Majamaa K (2003) Mitochondrial DNA polymorphisms associated with longevity in a Finnish population. Hum Genet 112:29–33

    Article  PubMed  CAS  Google Scholar 

  • Ng PC, Henkoff JG, Henikoff S (2000) PHAT: a transmembrane-specific substitution matrix. Bioinformatics 16:760–766

    Article  PubMed  CAS  Google Scholar 

  • Parker WD, Parks JK (2005) Mitochondrial ND5 mutations in idiopathic Parkinson’s disease. Biochem Biophys Res Commun 326:667–669

    Article  PubMed  CAS  Google Scholar 

  • Parker WD, Filley CM, Parks JK (1990) Cytochrome oxidase deficiency in Alzheimer’s disease. Neurol 40:1302–1303

    Google Scholar 

  • Parker WD, Parks JK, Filley CM, Kleinschmidt-Demasters BK (1994) Electron transport chain defects in Alzheimer’s disease brain. Neurol 44:1090–1096

    Google Scholar 

  • Persson B, Argos P (1994) Prediction of transmembrane segments in proteins utilizing multiple sequence alignments. J Mol Biol 237:182–192

    Article  PubMed  CAS  Google Scholar 

  • Richards M, Macaulay V, Hickey E, Vega E, Sykes B, Guida V, Rengo C, Sellitto D, Cruciani F, Kivisild T, Villems R, Thomas M, Rychkov S, Rychkov O, Rychkov Y, Golge M, Dimitrov D, Hill E, Bradley D, Romano V, Cali F, Vona G, Demaine A, Papiha S, Triantaphyidis C, Stefanescu G, Hatina J, Belledi M, Di renzo A, Novelletto A, Oppenheim A, Norby S, Al-Zaheri N, Santachiara-Benerecetti S, Scozzari R, Torroni A, Bandelt H-J (2000) Tracing European founder lineages in the Near Eastern mtDNA pool. Am J Hum Genet 67:1251–1277

    PubMed  CAS  Google Scholar 

  • Rose G, Passarino G, Carrieri G, Altomare K, Greco V, Bertolini S, Bonafe M, Franceschi C, De Benedictis G (2001) Paradoxes in longevity: sequence analysis of mtDNA haplogroup J in centenarians. Eur J Hum Genet 9:701–707

    Article  PubMed  CAS  Google Scholar 

  • Roubertoux PL, Sluyter F, Carlier M, Marcet B, Maarouf-Veray F, Cherif C, Marcian C, Arrechi P, Godin F, Jamon M, Verrier B, Cohen-Salmon C (2003) Mitochondrial DNA modifies cognition in interaction with the nuclear genome and age in mice. Nat Genet 35:65–69

    Article  PubMed  CAS  Google Scholar 

  • Schon EA, Manfredi G (2003) Neuronal degeneration and mitochondrial dysfunction. J Clin Invest 111:303–312

    PubMed  CAS  Google Scholar 

  • Schon EA, Shoubridge EA, Moraes CT (1998) Cybrids in Alzheimer’s disease: a cellular model of the disease? Neurology 51:326–327

    PubMed  CAS  Google Scholar 

  • Simonian NA, Hyman BT (1993) Functional alterations in Alzheimer’s disease: diminution of cytochrome oxidase in the hippocampal formation. J Neuropath Exp Neurol 52:580–585

    Article  PubMed  CAS  Google Scholar 

  • Simonian NA, Hyman BT (1994) Functional alterations in Alzheimer’s disease: selective loss of mitochondrial-encoded cytochrome oxidase mRNA in the hippocampal formation. J Neuropath Exp Neurol 53:508–512

    Article  PubMed  CAS  Google Scholar 

  • Smith MA, Drew KL, Nunomara A, Takeda A, Hirai K, Zhu X, Atwood CS, Raina AK, Rottkamp CA, Sayre LM, Friedland RP, Perry G (2002) Amyloid-β, tau alterations and mitochondrial dysfunction in Alzheimer disease: the chickens or the eggs? Neurochem Int 40:527–531

    Article  PubMed  CAS  Google Scholar 

  • Swerdlow RH, Parks JK, Cassarino DS, Maguire DJ, Maguire RS, Bennett JPJ, Davis RE, Parker WD (1997) Cybrids in Alzheimer’s disease: a cellular model of the disease? Neurology 49:918–925

    PubMed  CAS  Google Scholar 

  • Thomas PD, Kejariwal A (2004) Coding single-nucleotide polymorphisms associated with complex vs. Mendelian disease: evolutionary evidence for differences in molecular effects. Proc Natl Acad Sci USA 101:15398–15403

    Article  PubMed  CAS  Google Scholar 

  • Trimmer PA, Swerdlow RH Parks JK, Keeney P, Bennett JP, Miller SW, Davis RE, Parker WD (2000) Abnormal mitochondrial morphology in sporadic Parkinson’s and Alzheimer’s disease cybrid cell lines. Exp Neurol 162:37–50

    Article  PubMed  CAS  Google Scholar 

  • Trimmer PA, Keeney PM, Borland MK, Simon FA, Almeida J, Swerdlow R, Parks JP, Parker WD, Bennett JP (2004) Mitochondrial abnormalities in cybrid cell models of sporadic Alzheimer’s disease worsen with passage in culture. Neurobiol Dis 15:29–39

    Article  PubMed  CAS  Google Scholar 

  • Valla J, Berndt JD, Gonzalez-Lima F (2001) Energy hypometabolism in posterior cingulate cortex of Alzheimer’s patients: superficial laminar cytochrome oxidase associated with disease duration. J Neurosci 21:4923–4930

    PubMed  CAS  Google Scholar 

  • Vilmi T, Moilanen JS, Finnila S, Majamaa K (2005) Sequence variation in the tRNA genes of human mitochondrial DNA. J Mol Evol 60:587–597

    Article  PubMed  CAS  Google Scholar 

  • van der Walt JM, Dementieva YA, Martin ER, Scott WK, Nicodemus KK, Kroner CC, Welsh-Bohmer KA, Saunders AM, Roses AD, Small GW, Schmechel DE, Doraisamy PM, Gilbert JR, Haines JL, Vance JM, Pericak-Vance MA (2004) Analysis of European mitochondrial haplogroups with Alzheimer disease risk. Neurosci Lett 365:28–32

    Article  PubMed  CAS  Google Scholar 

  • Zhu X, Raina AK, Perry G, Smith MA (2004) Alzheimer’s disease: the two-hit hypothesis. Lancet Neurol 3:219–226

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr. H. Payami (University of Oregon Health Science University) for providing some of the samples used for the present study. Dr. Eoin Fahy (MitoKor Inc.) assisted with data storage and analysis. This research was supported by a Wellcome Collaboration Grant (to D. M. T., N. H.), an MRC BioInformatics Fellowship (J. L. E.), and grant AGO P50-5131 from the National Institutes of Health (L. T.).

Author information

Authors and Affiliations

  1. Mitochondrial Research Group, School of Neurology, Neurobiology, and Psychiatry, The University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom

    Joanna L. Elson & Douglass M. Turnbull

  2. MitoKor Inc. (now MIGENIX Corp.), San Diego, CA, USA

    Corinna Herrnstadt & Gwen Preston

  3. Department of Neurosciences, University of California San Diego, San Diego, CA, USA

    Leon Thal

  4. Institute for the Health of the Elderly, Newcastle General Hospital, Newcastle upon Tyne, United Kingdom

    Christopher M. Morris & J. A. Edwardson

  5. Department of Neurology, Cornell University Medical College, New York, NY, USA

    M. Flint Beal

  6. MRC/University of Newcastle upon Tyne Development Centre for Clinical Brain Ageing, Newcastle upon Tyne, United Kingdom

    Douglass M. Turnbull

  7. MIGENIX Corp., Suite 210, 12780 High Bluff Drive, San Diego, CA, 92130, USA

    Neil Howell

  8. Department of Radiation Oncology, The University of Texas Medical Branch, Galveston, TX, USA

    Neil Howell

Authors
  1. Joanna L. Elson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Corinna Herrnstadt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gwen Preston
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Leon Thal
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Christopher M. Morris
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J. A. Edwardson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M. Flint Beal
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Douglass M. Turnbull
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Neil Howell
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Neil Howell.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Cite this article

Elson, J.L., Herrnstadt, C., Preston, G. et al. Does the mitochondrial genome play a role in the etiology of Alzheimer’s disease?. Hum Genet 119, 241–254 (2006). https://doi.org/10.1007/s00439-005-0123-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-005-0123-8

Keywords

Search

Navigation