Neuronal loss in Parkinson's disease (PD) is associated with aberrant mitochondrial function in dopaminergic (DA) neurons of the substantia nigra pars compacta. An association has been reported between PD onset and exposure to mitochondrial toxins, including the agrochemicals paraquat (PQ), maneb (MB), and rotenone (Rot). Here, with the use of a patient-derived stem cell model of PD, allowing comparison of DA neurons harboring a mutation in the α-synuclein (α-syn) gene ( SNCA-A53T) against isogenic, mutation-corrected controls, we describe a novel mechanism whereby NO, generated from SNCA-A53T mutant neurons exposed to Rot or PQ/MB, inhibits anterograde mitochondrial transport through nitration of α-tubulin (α-Tub). Nitration of α-Tub inhibited the association of both α-syn and the mitochondrial motor protein kinesin 5B with the microtubules, arresting anterograde transport. This was, in part, a result of nitration of α-Tub in the C-terminal domain. These effects were rescued by inhibiting NO synthesis with the NOS inhibitor Nω-nitro-L-arginine methyl ester. Collectively, our results are the first to demonstrate a gene by environment interaction in PD, whereby agrochemical exposure selectively triggers a deficit in mitochondrial transport by nitrating the microtubules in neurons harboring the SNCA-A53T mutation.-Stykel, M. G., Humphries, K., Kirby, M. P., Czaniecki, C., Wang, T., Ryan, T., Bamm, V., Ryan, S. D. Nitration of microtubules blocks axonal mitochondrial transport in a human pluripotent stem cell model of Parkinson's disease.
Keywords: anterograde transport; isogenic hiPSCs; neurodegeneration; reactive nitrogen species; tubulin nitration.