The role of the Wallerian axon-death pathway in neuronal and axonal vulnerability in Parkinson's disease (360G-Wellcome-210904_Z_18_Z)

Parkinson’s disease (PD) involves preferential loss of substantia nigra pars compacta (SNc) dopaminergic neurons and their projecting axons to the striatum. SNc neurons have huge, highly branched and vulnerable axons, whose distal ends are lost first in PD, so preventing this will be essential for any disease modifying therapy. Our preliminary data suggest the involvement of an axon-death pathway in PD shared with the loss of injured axons (Wallerian degeneration). The Wallerian pathway is initiated by loss of the activity of the essential NAD-biosynthetic enzyme NMNAT2 in axons. Crucially, axons expressing lower levels of NMNAT2 are more vulnerable, raising the possibility that SNc neuron and axon susceptibility in PD reflects a particular sensitivity to Wallerian pathway activation. To test this hypothesis, I will use cutting-edge research strategies from three leading laboratories in axon degeneration and Parkinson’s disease, combining expertise in mouse primary neuronal cultures, human iPSC-derived dopaminergic neurons and mouse and zebrafish in vivo models of PD. The proposed research will greatly advance our understanding of mechanisms of SNc neuron and axon death in PD. In the longer term, this work has significant clinical implications since axons are lost early in PD and the Wallerian pathway can be potently blocked.