title: A mitochondrial etiology of Alzheimer and Parkinson disease.
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.
  
  
  METHODS
  We argue that the available data on AD and PD can be incorporated into a single integrated paradigm based on mitochondrial genetics and pathophysiology.
  
  
  CONCLUSIONS
  Rare 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 tRNA(Gln) 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.
  
  
  CONCLUSIONS
  Therefore, 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.
authors.affiliation: Department of Biological Chemistry, Hewitt Hall, Irvine, CA 92697-3940, USA.
authors.forename: Pinar
authors.initials: P
authors.lastname: Coskun
authors.forename: Joanne
authors.initials: J
authors.lastname: Wyrembak
authors.forename: Samual E
authors.initials: SE
authors.lastname: Schriner
authors.forename: Hsiao-Wen
authors.initials: HW
authors.lastname: Chen
authors.forename: Christine
authors.initials: C
authors.lastname: Marciniack
authors.forename: Frank
authors.initials: F
authors.lastname: Laferla
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Wallace
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology* / Q000503:physiopathology; D000818:Animals; D006801:Humans; D008928:Mitochondria / Q000473:pathology; D028361:Mitochondrial Diseases / Q000209:etiology* / Q000503:physiopathology; D010300:Parkinson Disease / Q000209:etiology* / Q000503:physiopathology