The disease-causing tau V337M mutation induces tau hypophosphorylation and perturbs axon morphology pathways.

Tau aggregation is a hallmark of several neurodegenerative diseases, including Alzheimer's disease and frontotemporal dementia. There are disease-causing variants of the tau-encoding gene, MAPT, and the presence of tau aggregates is highly correlated with disease progression. However, the molecular mechanisms linking pathological tau to neuronal dysfunction are not well understood due to our incomplete understanding of the normal functions of tau in development and aging and how these processes change in the context of causal disease variants of tau. To address these questions in an unbiased manner, we conducted multi-omic characterization of iPSC-derived neurons harboring the MAPT V337M mutation. RNA-seq and phosphoproteomics revealed that both V337M tau and tau knockdown consistently perturbed levels of transcripts and phosphorylation of proteins related to axonogenesis or axon morphology. Surprisingly, we found that neurons with V337M tau had much lower tau phosphorylation than neurons with WT tau. We conducted functional genomics screens to uncover regulators of tau phosphorylation in neurons and found that factors involved in axonogenesis modified tau phosphorylation in both MAPT WT and MAPT V337M neurons. Intriguingly, the p38 MAPK pathway specifically modified tau phosphorylation in MAPT V337M neurons. We propose that V337M tau might perturb axon morphology pathways and tau hypophosphorylation via a "loss of function" mechanism, which could contribute to previously reported cognitive changes in preclinical MAPT gene carriers.

Divalent copper complexes as influenza A M2 inhibitors.

New M2 blockers effective against the ubiquitous amantadine-resistant S31N M2 mutation in influenza A are needed. Six copper complexes, 2, 4, 6, 8, 9, and 10, were synthesized and found to block both wild type and S31N M2. Free Cu2+ also blocks M2 S31N but not S31N/H37A. The copper complexes do not block M2 H37A (either S31 or S31N). The complexes were effective against three influenza A strains in cell-culture assays, but less toxic to cells than CuCl2. For example 4, Cu(cyclooctylamineiminodiacetate), which was stable at pH > 4 in the buffers used, had an EC50 against A/Calif/07/2009 H1N1 of 0.7 ± 0.1 µM with a CC50 of 147 µM (therapeutic index, averaged over three strains, 67.8). In contrast, CuCl2 had an EC50 of 3.8 ± 0.9 µM and CC50 of 19 µM. Because M2 H37 is highly conserved, these complexes show promise for further testing as drugs against all strains of influenza A.