The PINK1-VCP-p47 pathway protects against tau-induced dendritic shrinkage in cortical neurons through interaction...

Microtubule associated protein tau (tau) contributes to the pathogenesis of AD and some forms of Frontotemporal Lobar Dementia wherein dendritic simplification is strongly related to cognitive dysfunction. Loss of function mutations in PTEN-induced kinase 1 (PINK1) cause recessive early-onset Parkinson's disease with dementia, and reduced wild-type PINK1 expression is observed in Alzheimer's disease (AD). We previously found that PINK1 interacts with valosin-containing protein (VCP) and promotes phosphorylation of the VCP co-factor NSFL1C (p47). This study was designed to test the hypothesis that PINK1 rescues tau-induced dendritic simplification through the VCP-p47 pathway, and to define neuroprotective mechanisms downstream of p47 phosphorylation. Mouse primary cortical neurons were transfected with 2N4R-Tau and plasmids encoding components of the PINK1-VCP-p47 signaling pathway and the impact on Tau-mediated dendritic injury was assessed. Immunoprecipitation-mass spectrometry, immunoblotting, RNAi and Sholl analysis were performed to define downstream mechanisms of neuroprotection. Tau-induced dendritic shortening and simplification was fully rescued by co-expression of PINK1, VCP, p47 or the p47-S176D phosphomimic (p47D), but not by the non-phosphorylatable p47-S176A (p47A) variant. Pathway analysis showed enhanced interactions of p47D with proteins in the Rho-GTPase pathway. Immunoprecipitation confirmed that STIP1 interacts with p47D to a significantly higher degree than p47A. Overexpression of STIP1 rescued tau-mediated dendritic simplification. Moreover, STIP1 siRNA impaired the neuroprotective effects of both PINK1 and p47D, indicating an essential role in the PINK1-p47D neuroprotection pathway. The current study highlights a novel PINK1-(phospho)p47-STIP1 signaling axis that promotes dendritic complexity and protects against tau-induced neurodegeneration in cortical neurons.