Prostate-derived Sterile 20-like Kinases (PSKs/TAOKs) Phosphorylate Tau and are Activated in Tangle-bearing Neurons in Alzheimer's Disease

In Alzheimers disease (AD) the microtubule-associated protein tau is highly phosphorylated and aggregates into characteristic neurofibrillary tangles (NFTs). Prostate-derived sterile 20-like kinases (PSKs) 1 and 2, members of the sterile 20 family of kinases, have been shown to regulate microtubule stability and organization. Here, we show that tau is a good substrate for PSK1 and PSK2 phosphorylation, with mass spectrometric analysis of phosphorylated tau revealing more than forty tau residues as targets of these kinases. Notably, phosphorylated residues include motifs located within the microtubule-binding repeat domain on tau (S262, S324 and S356), sites which are known to regulate tau-microtubule interactions. PSK catalytic activity is enhanced in the entorhinal cortex and hippocampus, areas of the brain which are most susceptible to Alzheimers pathology, in comparison to the cerebellum, which is relatively spared. Activated PSK is associated with NFTs, dystrophic neurites surrounding neuritic plaques, neuropil threads and granulovacuolar degeneration bodies in AD brain. By contrast, activated PSKs and phosphorylated tau are rarely detectible in control human brain. Our results demonstrate that tau is a substrate for PSK and suggest that this family of kinases could contribute to the development of AD pathology and dementia.