Effects of PARP-1 signaling and conjugated linoleic acid on brain cell bioenergetics and survival

Simple item page
dc.contributor.authorHunt, Waylon T.
dc.contributor.examiningcommitteeGlazner, Gordon (Pharmacology and Therapeutics) Anderson, Hope (Pharmacy) Amara, Francis (Biochemistry and Medical Genetics) Alano, Conrad (University of California, San Francisco)en_US
dc.contributor.supervisorAnderson, Christopher (Pharmacology and Therapeutics)en_US
dc.date.accessioned2012-01-11T18:10:44Z
dc.date.available2012-01-11T18:10:44Z
dc.date.issued2010-10-01
dc.degree.disciplinePharmacology and Therapeuticsen_US
dc.degree.levelDoctor of Philosophy (Ph.D.)en_US
dc.description.abstractGlutamate is the primary excitatory neurotransmitter in the central nervous system. Extracellular glutamate concentrations are tightly regulated to avoid over-stimulation of glutamate receptors, which leads to a cascade of deleterious processes collectively known as excitotoxicity. Excitotoxicity is common to several neurodegenerative disorders and CNS injuries, including stroke and Alzheimer’s disease (AD). The projects described in this thesis were designed to uncover novel protective pathways in excitotoxic neurodegeneration. Excessive activation of the DNA repair enzyme, poly(ADP-ribose) polymerase-1 (PARP-1), is a convergence point for neuron death signaling in excitotoxic pathways. In AD, the peptide amyloid-β1-42 (Aβ1-42) is aberrantly produced, leading to excitotoxic neuron death in vitro. To investigate links between Aβ1-42 and PARP, we treated cultured cortical neurons with Aβ1-42 and determined whether PARP-1 contributes to neuron death. Increased neuron death was observed after Aβ1-42 exposure. A non-selective PARP-1/2 inhibitor significantly reduced Aβ1-42-induced death while elimination of PARP-1 alone was not neuroprotective. This suggests that PARP-2 or combined effects of PARP-1 and PARP-2 are required for Aβ1-42-induced neuron death. A hallmark of PARP over-activation is depletion of intracellular NAD+ and ATP levels, yet nearly all studies examining adenine nucleotide levels use separate biochemical samples to measure nucleotides individually. We developed two HPLC methods for simultaneous separation of NAD+, ATP, ADP and AMP. We determined that PARP-1 activation in astrocytes leads to near complete NAD+ depletion, followed by partial loss of ATP pools and total adenine nucleotide pools. Finally, we hypothesized that conjugated linoleic acid (CLA), a naturally occurring polyunsaturated fatty acid, is capable of enhancing neuron survival after an excitotoxic insult. Cultured cortical neurons were exposed to glutamate in the presence and absence of CLA. CLA levels likely achievable in human plasma and brain tissue during dietary supplementation regimens, protected neurons against glutamate excitotoxicity when given during or up to five hours after glutamate exposure. Several markers of mitochondrial damage and intrinsic apoptosis were examined. CLA stabilized mitochondrial membrane potential and permeability, shedding light on the mechanism of CLA neuroprotection. Overall, our research suggests a role for PARP in Aβ1-42 toxicity and identifies a novel role for CLA in neuroprotection following excitotoxicity.en_US
dc.description.noteFebruary 2012en_US
dc.identifier.citationHunt WT, Anderson, HD and Anderson CM. (2010) Protection of cortical neurons from excitotoxicity by treatment with conjugated linoleic acid after glutamate exposure. J Neurochem. 115(1):123-30.en_US
dc.identifier.citationTang KS, Suh SW, Alano CC, Shao Z, Hunt WT, Swanson RA, Anderson CM. (2010) Astrocyte poly(ADP-ribose) polymerase-1 (PARP-1) activation leads to bioenergetic depletion and inhibition of glutamate uptake capacity. Glia 58 446:457.en_US
dc.identifier.citationHunt WT, Salins P, Anderson CM, Amara F. (2010) Neuroprotective role of statins in Alzheimer Disease: Anti-apoptotic signaling. Bentham Open Neuroscience Journal 2010 4:13-22.en_US
dc.identifier.urihttp://hdl.handle.net/1993/5070
dc.language.isoengen_US
dc.publisherJohn Wiley and Sonsen_US
dc.publisherJohn Wiley and Sonsen_US
dc.publisherBentham Openen_US
dc.rightsopen accessen_US
dc.subjectCLAen_US
dc.subjectNeuronsen_US
dc.subjectbioenergeticsen_US
dc.subjectPARP-1en_US
dc.subjectAstrocytesen_US
dc.subjectStrokeen_US
dc.subjectAlzheimer'sen_US
dc.subjectexcitotoxicityen_US
dc.titleEffects of PARP-1 signaling and conjugated linoleic acid on brain cell bioenergetics and survivalen_US
dc.typedoctoral thesisen_US
Files
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
hunt_waylon.pdf
Size:
2.54 MB
Format:
Adobe Portable Document Format
Description:
Download
License bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
license.txt
Size:
2.25 KB
Format:
Item-specific license agreed to upon submission
Description:
Download
Collections
FGS - Electronic Theses and Practica