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Program Project on the Pathogenesis and Treatment of Parkinson's Disease

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Annual rept. 1 Dec 2005-30 Nov 2006

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This proposal represents the authors continuing efforts to investigate the molecular mechanisms of Parkinsons disease PD, a progressive neurodegenerative disorder that affects about 1 million people in the United States alone. Recent evidence suggests that inflammation plays a major role in the progressive nature of this disease. Thus, they are investigating the contributions of several pro-inflammatory enzymes that they found up-regulated in microglia following the use of 1-methyl-4-phenyl-1,2,3,6-tetrahydropiridine MPTP, the neurotoxin that is the cornerstone of PD research. They found that the number of substantia nigra pars compacta SNpc dopaminergic neurons DA in MPTP-treated IL-1 beta and IL-1R1 knockout mice did not differ from their nonknockout litter mates. This suggests that IL-1 beta and IL-1R1 may not be involved in the inflammatory response related to the necrotic form of neuronal death characteristic of the acute MPTP dosing schedule. However, they did note that cyclooxygenase-2 COX-2 and cPLA2 are both up-regulated in SNpc DA neurons following acute MPTP. Because the acute MPTP dosing schedule is quite harsh, Core B characterized a subacute MPTP model of PD and found that this model exhibits at least 3 forms of neuronal death in the SNpc that are time-dependent necrosis, apoptosis, and autophagy. This subacute model is closer to human PD in that it does not present an immediate end-stage situation characteristic of many neurotoxin-based PD models. The authors also have found in this subacute model that the number of SNpc DA neurons in MPTP-treated IL-1 beta and IL-1R1 knockout mice did not differ from their nonknockout litter mates during the inflammatory process, which is somewhat confusing. Thus, they are now using their neuronalglial cultures and their neuronal- and glial-conditioned media to sort out the mechanisms involved in the initiation of the inflammatory response related to SNpc DA neuronal death.

Subject Categories:

  • Biochemistry
  • Genetic Engineering and Molecular Biology
  • Anatomy and Physiology
  • Medicine and Medical Research

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