Dopaminergic midbrain neurons are the prime target for mitochondrial DNA deletions.
Mitochondrial dysfunction is a consistent finding in neurodegenerative disorders like Alzheimer's (AD) or Parkinson's disease (PD) but also in normal human brain aging. In addition to respiratory chain defects, damage to mitochondrial DNA (mtDNA) has been repeatedly reported in brains from AD and PD patients. Most studies though failed to detect biologically significant point mutation or deletion levels in brain homogenate. By employing quantitative single cell techniques, we were recently able to show significantly high levels of mtDNA deletions in dopaminergic substantia nigra (SN) neurons from PD patients and age-matched controls. In the present study we used the same approach to quantify the levels of mtDNA deletions in single cells from three different brain regions (putamen, frontal cortex, SN) of patients with AD (n = 9) as compared to age-matched controls (n = 8). There were no significant differences between patients and controls in either region but in both groups the deletion load was markedly higher in dopaminergic SN neurons than in putamen or frontal cortex (p < 0.01; ANOVA). This data shows that there is a specific susceptibility of dopaminergic SN neurons to accumulate substantial amounts of mtDNA deletions, regardless of the underlying clinical phenotype.
Bender
Andreas
A
Dept. of Neurology, Mitochondrial Neurogenetics, University of Munich, Marchioninistr. 15, 81377, Munich, Germany. andreas.bender@med.uni-muenchen.de
Schwarzkopf
Rachel-Maria
RM
McMillan
Anja
A
Krishnan
Kim J
KJ
Rieder
Gabriele
G
Neumann
Manuela
M
Elstner
Matthias
M
Turnbull
Douglas M
DM
Klopstock
Thomas
T
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D016022:Case-Control Studies; D004272:DNA, Mitochondrial / Q000235:genetics*; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D042282:Microdissection / Q000379:methods; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism*; D017384:Sequence Deletion / Q000235:genetics*; D013378:Substantia Nigra / Q000473:pathology*
D004272:DNA, Mitochondrial; D004298:Dopamine