Mitochondrial dysfunction, oxidative stress, impairment of proteasomal function and protein aggregationare the common molecular basis of the loss of dopaminergic (DA) neurons in the substantia nigra parscompacta (SNpC). Mitochondrial dysfunction and increased vulnerability of dopaminergic (DA) neuronsto oxidative stress has specifically implicated in the pathogenesis of PD. Molecular sources for reactiveoxygen species (ROS) in PD however have not been clearly elucidated. ROS are physiologic byproductof several organelles and biological reactions including mitochondria, peroxisomes, cytochrome P-450,xanthine oxidase, cyclooxygenase and NO synthase. A family of NADPH oxidase (NOX) is the first enzyme complex discovered which is specialized togenerate superoxide. Nox homologues have been specifically identified in the central nervous system(CNS) and shown to play major roles in development, memory, neuronal signaling, and cardiovascularhomeostasis. At the same time, an equally significant body of evidence has shown that overproduction ofROS by abnormal Nox activation may also contribute to neurodegeneration. Moreover, recent studiesindicate that mitochondria play a role in NADPH oxidase-mediated (especially NOX1) superoxidegeneration. The interplay between mitochondria and NOX1 amplifies ROS generation and results in celldeath. This suggests that two cardinal factors, mitochondrial dysfunction and oxidative stress, implicatedin the PD pathogenesis may link each other through the NOX system. Our preliminary results demonstrate that DA cells are equipped with the NOX-mediated superoxidegeneration system. NOX1 was induced by oxidative stress such as 6-OHDA and mitochondrial toxin,rotenone. Inhibition of Rac1, a key component for Nox activation or Nox1 knockdown led to protection ofsubstantia nigra DA neurons from 6-OHDA administration. LRRK2 mutation (G2019S) increased ROSgeneration in N27 DA cells and apocynin, a specific NADPH oxidase inhibitor reduced ROS productionelicited by LRRK2 mutant. These proposed studies will investigate 1) whether inhibition of NOX1 leads toDA neuroprotection, 2) the molecular mechanism underlying DA cell-specific transcriptional regulation ofNOX1 and mitochondrial involvement and 3) whether LRRK2 mutations affect the activation of NOX-mediated ROS production and consequential DA neurodegeneration.
Mitochondrial dysfunction and oxidative stress are strongly implicated in the pathogenesis of PD. The overall goal of this proposed study is to define the role of NADPH oxidase, the specialized superoxide generation system in degeneration of the dopaminergic nigrostriatal pathway. We will investigate whether mitochondria play a key role in the NOX system activation and the intervention of the NOX system prevents DA neurodegeneration caused by mitochondrial impairment. Additionally, the study on the interaction between LRRK2 mutations and the NOX activation may identify common molecular pathways involved in the pathogenesis of PD. Collectively, these results will help us to understand cellular mechanism governing the vulnerability of the DA nigrostriatal pathway to oxidative stress and lead to the development of novel therapeutic target.
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