Role of microglial NMDA receptor-initiated PARP-1/TRPM2 signaling in driving chronic neuroinflammation

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dc.contributor.authorRaghunatha, Prajwal
dc.contributor.examiningcommitteeSiddiqui, Tabrez (Physiology and Pathophysiology) Anderson, Chris (Pharmacology and Therapeutics)en_US
dc.contributor.supervisorKauppinen, Tiina (Pharmacology and Therapeutics) Jackson, Michael (Pharmacology and Therapeutics)en_US
dc.date.accessioned2019-08-26T16:59:21Z
dc.date.available2019-08-26T16:59:21Z
dc.date.issued2019-08-22en_US
dc.date.submitted2019-08-22T15:09:13Zen
dc.degree.disciplinePharmacology and Therapeuticsen_US
dc.degree.levelMaster of Science (M.Sc.)en_US
dc.description.abstractAn important component of neurodegenerative disorders, like Alzheimer’s disease (AD), is the prolonged inflammatory response driven by continuous microglial poly (ADP-ribose) polymerase-1 (PARP-1) activation. However, mechanisms that promote sustained microglial PARP-1 activation and maintaining microglial activity remains elusive. But we know that PARP-1 enzymatic activity requires Ca2+ influx, a process that is independent of DNA damage, and this could be through microglial N-methyl D-aspartate receptors (NMDARs). Notably, PARP-1 mediated ADP-ribose production causes activation of Ca2+ permeable non-selective cation channel, transient receptor potential melastatin-2 (TRPM2). Hence, we hypothesize that NMDAR activation by amyloid beta oligomers (AβO) or NMDA initiates PARP-1 mediated ADPR production and TRPM2 activation. This in-turn leads to TRPM2-dependent, self-sustaining PARP-1 activation, which promotes pro-inflammatory responses. Primary microglia treated with AβO and NMDA were assessed for functional TRPM2 currents using whole cell voltage-clamp electrophysiology. Using nitric oxide assay and qRT-PCR, AβO/NMDA treated microglia were also evaluated to identify the contribution of NMDAR/PARP-1/TRPM2 in promoting pro-inflammatory responses. Our findings, demonstrates that glutamate signaling via NMDARs, promoting detrimental microglial responses, suggests a unifying mechanism linking elevated glutamate levels, associated for example with AD, hypoxic-ischemic injury, or traumatic brain injury, to chronic neuroinflammation.en_US
dc.description.noteOctober 2019en_US
dc.identifier.urihttp://hdl.handle.net/1993/34091
dc.language.isoengen_US
dc.rightsopen accessen_US
dc.subjectAlzheimer's Diseaseen_US
dc.subjectMicrogliaen_US
dc.subjectTRPM2en_US
dc.subjectNMDARen_US
dc.subjectPARP-1en_US
dc.subjectNeuroinflamamtionen_US
dc.titleRole of microglial NMDA receptor-initiated PARP-1/TRPM2 signaling in driving chronic neuroinflammationen_US
dc.typemaster thesisen_US
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