Tau phosphorylation increases in symptomatic mice overexpressing A30P α-synuclein

Abstract

Mice overexpressing mutant α-synuclein develop a progressive loss of motor function associated with the accumulation of aggregated α-synuclein in neurons of the brainstem. Recent reports suggest that tau pathology might also be associated with Parkinson disease (PD) and aggregation of α-synuclein. We now report that mice overexpressing A30P α-synuclein develop abnormally phosphorylated tau in parallel with the accumulation of aggregated α-synuclein. Enhanced phosphorylation of tau occurs only in symptomatic mice that also harbor abundant aggregated α-synuclein. The increased phosphorylation of tau occurs at S396/404 and S202 as shown by immunoblotting and immunocytochemical studies with the antibodies PHF-1 and AT8. Neurons that accumulated α-synuclein occurred in the dorsal brainstem and did not show strong colocalization with neurons that showed abnormal tau phosphorylation, which largely occurred in the ventral brainstem. Aggregation of α-synuclein and phosphorylation of tau are associated with increased levels of phosphorylated c-jun kinase (JNK), which is a stress kinase known to phosphorylate tau protein. These results suggest that α-synuclein pathology can stimulate early pathological changes in tau.