Mechanisms of Observed Neuroprotection of Dopaminergic Neurons in Wallerian Degeneration Slow (WldS) Mice

An emerging hypothesis in Parkinson's disease (PD) is that dopaminergic (DA) neurons degenerate through a " dying back " axonopathy wherein degeneration begins in the distal axon and progresses over time towards the cell body. Impaired axonal transport also appears to play an early, pivotal role in PD. Thus processes that delay axonal transport dysfunction and/or axonal degeneration might slow PD progression. Previously, we and others have found that the Wld S mouse mutant (" Wallerian degeneration-slow "), which exhibits delayed axonal degeneration after peripheral axonopathy, also protects DA terminal fields from the PD-mimetics 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) in vivo. To understand the mechanisms underlying Wld S-mediated axonal protection, we tested whether Wld S rescued DA neurons in vitro after treatment with either MPP + , the active component of MPTP, or 6-OHDA. Wld S , but not its component parts, UbE4b and Nmnat1, robustly rescued neurites in dissociated DA cultures following either MPP + or 6-OHDA treatment. To extend these results, compartmented chambers were developed such that axons could be segregated from cell bodies and dendrites. Using these devices, we found that MPP + impaired mitochondrial, but not synaptic vesicle transport, in DA axons and that Wld S rescued MPP +-mediated impairment of mitochondrial transport in DA axons. Mechanistically, this appears to be due to Wld S-mediated protection from toxin-induced loss of mitochondrial membrane potential. These results extend Wld S protection to CNS DA neurons and suggest that Wld S confers a gain-of-function phenotype that attenuates mitochondrial dysfunction. This study, together with the large amount of evidence suggesting PD is associated with axonal " dying-back " , also underscores the necessity of developing therapeutics aimed at axons as well as cell bodies so as to preserve circuitry and function.