The etiology of idiopathic Parkinson's disease (PD) has not been elucidated, but roles for both genetic and environmental factors are hypothesized. It is postulated that endogenous MPP+ -analogs, such as neurotoxic N-methylated beta-carbolines (MeBCs+), may contribute to disease pathogenesis. Hypothesis: MeBCs+ are actively accumulated into monoaminergic neurons via the dopamine, norepinephrine, and serotonergic transporters. Therein, MeBCs+ cause oxidative stress, which mediates cellular dysfunction and death. System: Parental LLC-PK1 cells that lack monoamine transporters and LLC-PK1 cells exposed to the MeBC+, 2-methylnorharmanium iodide and 2,9-N, N-dimethylnorharmaniusm iodide.
Aim 1 : Characterize MeBC+-induced cytotoxicity as a function of time, MeBC+ concentration and expression of individual monoamine transporters.
Aim 2 : Compareoxidatively-damaged proteins, lipids, and DNA in MeBC+-exposed parental and transporter-expressing LLC-PK1 cultures. Significance: Oxidative stress is evident in PD; primarily affected is the dopaminergic system, but noradrenergic and serotonergic nuclei also exhibit pathology. These observations may be due to active agents in PD; results are fundamental to the development of therapies that could slow the progression of PD by reducing MdBC+ uptake and consequent oxidative damage.
|Keskin, Derin B; Marshall, Brendan; Munn, David et al. (2007) Decreased protein nitration in macrophages that overexpress indoleamine 2, 3-dioxygenase. Cell Mol Biol Lett 12:82-102|
|Gearhart, Debra A; Toole, Patricia F; Warren Beach, J (2002) Identification of brain proteins that interact with 2-methylnorharman. An analog of the parkinsonian-inducing toxin, MPP+. Neurosci Res 44:255-65|