A mitochondrial etiology of Alzheimer and Parkinson disease

• Published in: Biochimica et biophysica acta 2012-05, Vol.1820 (5), p.553-564
• Main Authors: Coskun, Pinar, Wyrembak, Joanne, Schriner, Samual E., Chen, Hsiao-Wen, Marciniack, Christine, LaFerla, Frank, Wallace, Douglas C.
• Format: Article
• Language: English
• Subjects: 3XTg-AD Mouse; Alzheimer Disease; Alzheimer Disease - etiology; Alzheimer Disease - physiopathology; Animals; brain; Down syndrome; etiology; females; genomics; Humans; males; messenger RNA; metabolism; mice; Mitochondria; Mitochondria - pathology; Mitochondrial Diseases - etiology; Mitochondrial Diseases - physiopathology; mitochondrial DNA; mtDNA; mutation; Oxidative phosphorylation; Parkinson Disease; Parkinson Disease - etiology; Parkinson Disease - physiopathology; pathophysiology; risk factors
• ISSN: 0304-4165; 0006-3002; 1872-8006; 0006-3002
• DOI: 10.1016/j.bbagen.2011.08.008

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. We argue that the available data on AD and PD can be incorporated into a single integrated paradigm based on mitochondrial genetics and pathophysiology. 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 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. 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. ► We reviewed mitochondrial involvement in AD and PD pathophysiology and presented unpublished evidence for mitochondrial defect in AD animal model and PD patients.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.