Parkinsonian Neurotoxin 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and α-Synuclein Mutations Promote Tau Protein Phosphorylation at Ser262 and Destabilize Microtubule Cytoskeleton in Vitro

In Parkinson disease (PD) brain, a progressive loss of dopaminergic neurons leads to dopamine depletion in the striatum and reduced motor function. Lewy bodies, the characteristic neuropathological lesions found in the brain of PD patients, are composed mainly of alpha-synuclein protein. Three point mutations in the alpha-synuclein gene are associated with familial PD. In addition, genome-wide association studies indicate that alpha-synuclein and Tau protein synergistically increase disease susceptibility in the human population. To determine the mechanism by which alpha-synuclein and Tau act together, we have used PD-causing neurotoxin MPTP and pathogenic alpha-synuclein mutants A30P, E46K, and A53T as models. We found that exposure of human neuroblastoma M17 cells to MPTP enhances the intracellular alpha-synuclein protein level, stimulates Tau protein phosphorylation at Ser(262), and induces apoptosis. In mouse brain, ablation of alpha-synuclein function significantly suppresses Tau phosphorylation at Ser(262). In vitro, alpha-synuclein binds to phosphorylated Ser(214) of Tau and stimulates PKA-catalyzed Tau phosphorylation at Ser(262). PD-associated alpha-synuclein mutations increase alpha-synuclein binding to Tau and stimulate Tau phosphorylation at Ser(262). In HEK-293 cells, alpha-synuclein and its all PD-associated mutants destabilize the microtubule cytoskeleton in a similar extent. In contrast, when co-expressed with Tau, these PD-associated mutants destabilize microtubules with significantly higher potency than WT. Our results demonstrate that alpha-synuclein is an in vivo regulator of Tau protein phosphorylation at Ser(262) and suggest that PD-associated risk factors such as environmental toxins and alpha-synuclein mutations promote Tau phosphorylation at Ser(262), causing microtubule instability, which leads to loss of dopaminergic neurons in PD brain.