WldS but not Nmnat1 protects dopaminergic neurites from MPP+ neurotoxicity

Using mutant mice and lentiviral transduction of dopaminergic neurons, the present findings demonstrate that WldS but not Nmnat1, Nmnat3, or cytoplasmically-targeted Nmnat1 protects dopamine axons from the parkinsonian mimetic N-methyl-4-phenylpyridinium (MPP+). Moreover, NAD+ synthesis is not required since enzymatically-inactive WldS still protects. In addition, NAD+ by itself is axonally protective and together with WldS is additive in the MPP+ model.Our data suggest that NAD+ and WldS act through separate and possibly parallel mechanisms to protect dopamine axons. As MPP+ is thought to impair mitochondrial function, these results suggest that WldS might be involved in preserving mitochondrial health or maintaining cellular metabolism.Parkinson's disease (PD) is the second most common neurodegenerative disorder in the U.S., affecting 1-2% of people over the age of 55. Characterized by loss of dopaminergic neurons in the substantia nigra (SN) [1,2], the cardinal motor symptoms of PD include resting tremor, bradykinesia, rigidity, and abnormal gait [3,4]. Another characteristic of PD is its late onset and progressive nature. Symptoms appear after 50-70% [5,6] of striatal dopamine has been depleted and 30-50% [7,8] of the nigral dopaminergic cells have died. Such studies suggest that the extent of striatal dopamine depletion is better correlated with the severity of PD symptoms than the loss of dopaminergic neurons in the SN [7].Data from PD-linked genetic mutations also support the notion that axonal pathology and/or dysfunction occurs prior to the loss of dopaminergic cell bodies. For example, α-synuclein pathology is seen in neurites before it is observed in PD-associated cell bodies [3,9]. α-synuclein mutants accumulate in the cell soma when overexpressed in cortical neurons, suggesting impaired axonal transport as well [10]. Moreover, transgenic models expressing the PD-linked mutant gene leucine rich repeat kinase 2 (LRRK2) also exhibit pronounced axonal loss