Mitogen-activated protein (MAP) kinases are a central component in signaling networks in a multitude of mammalian cell types. This review covers recent advances on specific functions of p38 MAP kinases in cells of the central nervous system. Unique and specific functions of the four mammalian p38 kinases are found in all major cell types in the brain. Mechanisms of p38 activation and downstream phosphorylation substrates in these different contexts are outlined and how they contribute to functions of p38 in physiological and under disease conditions. Results in different model organisms demonstrated that p38 kinases are involved in cognitive functions, including functions related to anxiety, addiction behavior, neurotoxicity, neurodegeneration, and decision making. Finally, the role of p38 kinases in psychiatric and neurological conditions and the current progress on therapeutic inhibitors targeting p38 kinases are covered and implicate p38 kinases in a multitude of CNS-related physiological and disease states.

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Mitogen-activated protein (MAP) kinase signaling is central to multiple cellular responses and processes. MAP kinase p38α is the best characterized member of the p38 MAP kinase family. Upstream factors and downstream targets of p38α have been identified in the past by conventional methods such as coimmunoprecipitation. However, a complete picture of its interaction partners and substrates in cells is lacking. Here, we employ a proximity-dependent labeling approach using biotinylation tagging to map the interactome of p38α in cultured 293T cells. Fusing the advanced biotin ligase BioID2 to the N-terminus of p38α, we used mass spectrometry to identify 37 biotin-labeled proteins that putatively interact with p38α. Gene ontology analysis confirms known upstream and downstream factors in the p38 MAP kinase cascade (e.g., MKK3, MAPKAPK2, TAB2, and c-jun). We furthermore identify a cluster of zinc finger (ZnF) domain-containing proteins that is significantly enriched among proximity-labeled interactors and is involved in gene transcription and DNA damage response. Fluorescence imaging and coimmunoprecipitation with overexpressed p38α in cells supports an interaction of p38α with ZnF protein XPA, a key factor in the DNA damage response, that is promoted by UV irradiation. These results define an extensive network of interactions of p38α in cells and new direct molecular targets of MAP kinase p38α in gene regulation and the DNA damage response. K E Y W O R D SBioID, biotinylation, interactome, MAP kinase, p38, p38α, protein-protein interaction, proximity-dependent labeling

Microtubule‐associated protein tau is a central factor in Alzheimer's disease and other tauopathies. However, the physiological functions of tau are unclear. Here, we used proximity‐labelling proteomics to chart tau interactomes in primary neurons and mouse brains in vivo. Tau interactors map onto pathways of cytoskeletal, synaptic vesicle and postsynaptic receptor regulation and show significant enrichment for Parkinson's, Alzheimer's and prion disease. We find that tau interacts with and dose‐dependently reduces the activity of N‐ethylmaleimide sensitive fusion protein (NSF), a vesicular ATPase essential for AMPA‐type glutamate receptor (AMPAR) trafficking. Tau‐deficient (tau−/−) neurons showed mislocalised expression of NSF and enhanced synaptic AMPAR surface levels, reversible through the expression of human tau or inhibition of NSF. Consequently, enhanced AMPAR‐mediated associative and object recognition memory in tau−/− mice is suppressed by both hippocampal tau and infusion with an NSF‐inhibiting peptide. Pathologic mutant tau from mouse models or Alzheimer's disease significantly enhances NSF inhibition. Our results map neuronal tau interactomes and delineate a functional link of tau with NSF in plasticity‐associated AMPAR‐trafficking and memory.

Hyperphosphorylation and deposition of tau in the brain characterizes frontotemporal dementia and Alzheimer’s disease. Disease-associated mutations in the tau-encoding MAPT gene have enabled the generation of transgenic mouse models that recapitulate aspects of human neurodegenerative diseases, including tau hyperphosphorylation and neurofibrillary tangle formation. Here, we characterized the effects of transgenic P301S mutant human tau expression on neuronal network function in the murine hippocampus. Onset of progressive spatial learning deficits in P301S tau transgenic TAU58/2 mice were paralleled by long-term potentiation deficits and neuronal network aberrations during electrophysiological and EEG recordings. Gene-expression profiling just prior to onset of apparent deficits in TAU58/2 mice revealed a signature of immediate early genes that is consistent with neuronal network hypersynchronicity. We found that the increased immediate early gene activity was confined to neurons harbouring tau pathology, providing a cellular link between aberrant tau and network dysfunction. Taken together, our data suggest that tau pathology drives neuronal network dysfunction through hyperexcitation of individual, pathology-harbouring neurons, thereby contributing to memory deficits.