The absence of Parkin in hTau mice leads to synaptic mitochondrial dysfunction, alterations to the synaptic proteome, and increased phosphorylated tau in the Hippocampus.

Amongst the major histopathological hallmarks in Alzheimer's disease are intracellular neurofibrillary tangles consisting of hyperphosphorylated and aggregated Tau, synaptic dysfunction, and synapse loss. We have previously shown evidence of synaptic mitochondrial dysfunction in a mouse model of Tauopathy that overexpresses human Tau (hTau). Here, we questioned whether the levels or activity of Parkin, an E3 ubiquitin ligase involved in mitophagy, can influence Tau-induced synaptic mitochondrial dysfunction. Here, we generated novel mouse strains by crossing hTau mice with either Parkin knockout mice or mice expressing mutant Parkin (Parkin, shown to lead to constitutively active Parkin in vitro). We found that Parkin levels are increased in synaptic mitochondria isolates from hTau compared to WT mice, suggesting increased mitophagy; while Parkin surprisingly led to decreased levels of Parkin in hTau mice. Furthermore, we showed that absence of Parkin in hTau mice leads to synaptic mitochondrial dysfunction; however, Parkin did not show functional rescuing effects. When compared to WT, proteomic analyses of synaptosomes demonstrated that hTau mice display protein changes that predict alterations to pathways related to mitochondrial metabolism, synaptic long-term potentiation, and synaptic calcium homeostasis. Both the absence of Parkin and expression of Parkin led to distinct changes in the hTau mouse synaptic proteome. Finally, we showed that Parkin-null hTau mice have higher levels of phosphorylated Tau in the hippocampal Dentate Gyrus, with no observable changes in hTau mice expressing Parkin. The data presented here illustrate the protective role that Parkin plays under Tau-induced mitochondrial and proteomic alterations, particularly at the synaptic level.