Neuroprotection by PXDNL, a Novel Heme-containing Peroxidase
Target Validation, 2009
Dysfunction of mitochondria in nerve cells contributes to the neurodegeneration of PD. When cells are infected by the CMV virus, they become resistant to certain mitochondrial toxins that may be important in causing PD. We found that CMV-infected cells produce very high levels of a protein called PXDNL about which very little is known. We have found that PXDNL is selectively found in substantia nigra neurons, and we hypothesize that increasing its levels will detoxify the free radicals produced by malfunctioning mitochondria and thereby protect these neurons.
This project will proceed in 2 phases. First, we will conduct in vitro studies using cultured neural cells. We will use molecular biological techniques to either reduce or increase the levels PXDNL in the cells, and then we will test their sensitivity to the mitochondrial toxin, rotenone, which causes a parkinsonian syndrome in rats. We expect that reducing PXDNL levels will increase the sensitivity to rotenone, and increasing PXDNL will make cells more resistant. If so, we begin the second phase of the work – in vivo studies in the rat rotenone model of PD. In these studies, we will use a virus to introduce into substantia nigra dopamine neurons of living rats genes that will reduce or increase PXDNL levels. We expect that rats with reduced PXDNL will be more susceptible to rotenone-induced parkinsonism and rats with increased PXDNL will be protected.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Impairment of mitochondrial function and oxidative damage produced by free radicals are believed to be important in causing the neurodegeneration of PD. We believe that PXDNL may protect against these toxic processes and, if so, it may open the way for a new approach to slowing or halting the progression of the disease.
We will test the idea that increasing the amount of PXDNL produced by dopamine neurons will protect them against a toxin that induces parkinsonism in rats. If we are correct – if this “target” is validated – we anticipate that gene therapy using PXDNL will provide a means to protect neurons and thereby retard the otherwise relentless progression of PD.
We have discovered a new gene, PXDNL, which is found selectively in the dopamine neurons of the substantia nigra. Although virtually nothing is known about PXDNL, there is reason to think it is a peroxidase enzyme, meaning that it may be able to detoxify the hydrogen peroxide and other oxidants that are found in dopamine neurons and which contribute to their degeneration. We found that increasing the amount of PXDNL in cells protects them against toxins, such as rotenone and paraquat, and reducing PXDNL makes the cells more vulnerable. Studies are ongoing to determine whether manipulating the levels of PXDNL via ‘gene therapy’ is beneficial in animal models of Parkinson’s disease. If so, this may be an attractive therapeutic approach.
Director, Pittsburgh Institute for Neurodegenerative Diseases at University of Pittsburgh
Location: Pittsburgh, Pennsylvania, United States