Nmnat Function in Axonal Neuroprotection
MJFF Research Grant, 2011
This grant builds upon the research from a prior grant:
Promising Outcomes of Original Grant:
In the previous application, we tested the hypothesis that gene delivery of NMNAT-1 would protect striatal innervation in 6-OHDA lesioned pre-clinical models and pre-clinical models receiving viral over expression of alpha synuclein. These experiments failed.
Objectives for Supplemental Investigation:
In our original application we wanted to combine NMNAT gene therapy with a trophic factor therapy that would preserve the cell bodies since NMNAT is only known for protection of axons. This part of the grant was not funded and only the NMNAT1 gene therapy studies against toxins were funded. This supplemental application will first demonstrate the protection of our mcherry-lenti-virus expressing the NMNAT gene upon cultured cells in vitro. Upon the successful completion of this milestone, we will then perform a second experiment. In this experiment, we will first inject AAV-GDNF to the substantia nigra. Then we will give the toxin in a manner in which the cell bodies will be preserved by the AAV-GDNF, but the innervation lost. Then we will provide the NMNAT gene in an attempt to protect the innervation. We will test the pre-clinical models on a battery of motor tests to associate any axonal preservation with functional neuroprotection.
Importance of This Research for the Development of a New PD Therapy:
Improvement in motor function in PD is not dependent upon preservation of cell bodies but rather preservation of striatal dopaminergic innervation. NMNAT-1 has been demonstrated to promote axonal preservation following a variety of injuries. NMNAT-1, combined with trophic factor therapy might be able to save dying neurons but also preserve and restore striatal dopamine innervation. This combined therapy might be a more promising experimental therapeutic approach than either therapy alone.
The purpose of this study is to determine whether NMAT, a protein that protects axons in the peripheral nervous system can similarly protect axons in the brain.† We first injected a trophic factor called neurturin in the area of the dopamine neurons in order to protect the cell bodies.† Then we created a lesion with 6-OHDA and delivered the NMAT with a viral vector.† We examined the pre-clinical modelís behavior using the stepping and cylinder tests. Neither tests demonstrated functional benefit. Then we examined the integrity of the dopamine system. The neurturin conferred protection of the dopamine cell bodies but this was not augmented by the NMAT.† The optical density of dopamine fibers were also examined. While the lesion caused a decrease in dopamine fiber staining, there were no differences in any of the experimental groups. Thus NMAT did not confer protection of the axons in the dopamine system.
The Jean Schweppe-Armour Professor of Neurological Sciences and Professor of Neurosurgery at Rush University Medical Center
Director of the Research Center for Brain Repair and Neuroscience Section Head at Rush University Medical Center
Location: Chicago, Illinois, United States