24-10-2012, 05:54 PM
Brain’s DNA Repair Response to Neurotoxicants
ABSTRACT
Parkinson’s Disease (PD) is associated with death of dopaminergic (DA) neurons in the substantia nigra (SN) of the brain.
Military personnel abroad are at a greater risk of exposure to pesticides and toxins which may selectively damage DA neurons
in the SN and increase the probability of development of Parkinson’s disease (PD) later in life. The toxins of interest are
mitochondrial poisons that create a bioenergetic crisis and generate toxic oxyradicals which damage macromolecules,
including DNA.We hypothesize that regulation macromolecules, including DNA.We hypothesize that regulation of the DNA
repair response within certain neurons of the SN (the pars compacta) may be a critical determinant for their vulnerability to
these neurotoxicants. We have measured regional differences in the brain’s capacity to increase repair of oxidized DNA
(indicated by oxyguanosine glycosylase (OGGl)activity) to three distinct chemical classes of neurotoxins (MPTP, two
mycotoxins, and an organochlorine pesticide). At the end of the first year of the project, we have found that the temporal and
spatial profile of OGG1 activity across brain regions elicited by each class of neurotoxicant is distinct and unique, but failure
to maintain a vigorous increase in OGGl and endogenous anti-oxidant activity in specific brain loci appears to be a shared
mechanism leading to neuronal injury in that region.