Joanne Wyrembak

Publications (2)8.74 Total impact

• Article: A mitochondrial etiology of Alzheimer and Parkinson disease

  Pinar Coskun, Joanne Wyrembak, Samual E. Schriner, Hsiao-Wen Chen, Christine Marciniack, Frank LaFerla, Douglas C. Wallace
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  ABSTRACT: Background The genetics and pathophysiology of Alzheimer Disease (AD) and Parkinson Disease (PD) appears complex. However, mitochondrial dysfunction is a common observation in these and other neurodegenerative diseases.Scope of reviewWe argue that the available data on AD and PD can be incorporated into a single integrated paradigm based on mitochondrial genetics and pathophysiology.Major conclusionsRare chromosomal cases of AD and PD can be interpreted as affecting mitochondrial function, quality control, and mitochondrial DNA (mtDNA) integrity. mtDNA lineages, haplogroups, such haplogroup H5a which harbors the mtDNA tRNAGln A8336G variant, are important risk factors for AD and PD. Somatic mtDNA mutations are elevated in AD, PD, and Down Syndrome and Dementia (DSAD) both in brains and also systemically. AD, DS, and DSAD brains also have reduced mtDNA ND6 mRNA levels, altered mtDNA copy number, and perturbed Aβ metabolism. Classical AD genetic changes incorporated into the 3XTg-AD (APP, Tau, PS1) mouse result in reduced forebrain size, life-long reduced mitochondrial respiration in 3XTg-AD males, and initially elevated respiration and complex I and IV activities in 3XTg-AD females which markedly declines with age.General significanceTherefore, mitochondrial dysfunction provides a unifying genetic and pathophysiology explanation for AD, PD, and other neurodegenerative diseases. This article is part of a Special Issue entitled Biochemistry of Mitochondria.Highlights► We reviewed mitochondrial involvement in AD and PD pathophysiology and presented unpublished evidence for mitochondrial defect in AD animal model and PD patients. ► The important risk factors as certain mtDNA haplotypes in AD and PD was discussed. ► Somatic mtDNA mutation accumulation differences in AD and DSAD compared to age matched controls revisited and unpublished data presented on PD. ► Novel sex dependent decline in mitochondrial bioenergetics were presented in 3xTg-AD model throughout the life span. ► Hence mitochondrial dysfunction provides rational explanation to understand neurodegenerative diseases’ pathophysiology.
  Biochimica et Biophysica Acta (BBA) - General Subjects 08/2011; 1820(5):553-564. · 5.00 Impact Factor
• Article: Systemic mitochondrial dysfunction and the etiology of Alzheimer's disease and down syndrome dementia.

  Pinar E Coskun, Joanne Wyrembak, Olga Derbereva, Goar Melkonian, Eric Doran, Ira T Lott, Elizabeth Head, Carl W Cotman, Douglas C Wallace
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  ABSTRACT: Increasing evidence is implicating mitochondrial dysfunction as a central factor in the etiology of Alzheimer's disease (AD). The most significant risk factor in AD is advanced age and an important neuropathological correlate of AD is the deposition of amyloid-beta peptide (Abeta40 and Abeta42) in the brain. An AD-like dementia is also common in older individuals with Down syndrome (DS), though with a much earlier onset. We have shown that somatic mitochondrial DNA (mtDNA) control region (CR) mutations accumulate with age in post-mitotic tissues including the brain and that the level of mtDNA mutations is markedly elevated in the brains of AD patients. The elevated mtDNA CR mutations in AD brains are associated with a reduction in the mtDNA copy number and in the mtDNA L-strand transcript levels. We now show that mtDNA CR mutations increase with age in control brains; that they are markedly elevated in the brains of AD and DS and dementia (DSAD) patients; and that the increased mtDNA CR mutation rate in DSAD brains is associated with reduced mtDNA copy number and L-strand transcripts. The increased mtDNA CR mutation rate is also seen in peripheral blood DNA and in lymphoblastoid cell DNAs of AD and DSAD patients, and distinctive somatic mtDNA mutations, often at high heteroplasmy levels, are seen in AD and DSAD brain and blood cells DNA. In aging, DS, and DSAD, the mtDNA mutation level is positively correlated with beta-secretase activity and mtDNA copy number is inversely correlated with insoluble Abeta40 and Abeta42 levels. Therefore, mtDNA alterations may be responsible for both age-related dementia and the associated neuropathological changes observed in AD and DSAD.
  Journal of Alzheimer's disease: JAD 01/2010; 20 Suppl 2:S293-310. · 3.74 Impact Factor