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Parkinson's disease-associated PINK1 G309D mutation increases abnormal phosphorylation of Tau.


PMID 25899925

Abstract

Mutations in PINK1 gene have been considered the second most common cause of Autosomal Recessive Parkinsonism (ARP). So far, different homozygous PINK1 mutations have been identified in different ARP patients. Abnormal hyperphosphorylation of tau leads to the loss of its biological activity. Multiple lines of evidence have demonstrated that hyperphosphorylated tau is associated with Alzheimer's disease and Parkinson's disease (PD). However, the effects of PD associated PINK1 mutations in tau phosphorylation are unknown. In this study, we investigated the effect of G309D PINK1 mutation in tau phosphorylation. Cells transfected with mutant G309D PINK1 exhibited a significant increase in the phosphorylation of tau protein at the PHF-1 (ser396/404) site. The levels of CDK5, an important activator of tau phosphorylation, did not change in mutant G309D PINK1 transfected cells, suggesting that CDK5 is not involved in tau phosphorylation induced by mutant G309D PINK1. Notably, we found that mutant G309D PINK1 significantly reduced phosphorylation of GSK3β at serine 9, suggesting that alterations in GSK3β activity play an essential role in mutant G309D PINK1-induced tau phosphorylation at the PHF-1 site. PP2A activity maintained consistent in mutant G309D PINK1 transfected cells, suggesting that the increased tau hyperphosphorylation is not ascribed to reduction in PP2A activity.