TTBK1 and CK1 inhibitors restore TDP-43 pathology and avoid disease propagation in lymphoblast from Alzheimer’s disease patients

Introduction TDP-43 proteinopathy in Alzheimer’s disease (AD) patients is recently emerging as a relevant pathomolecular event that may have been overlooked. Recent results immortalized lymphocytes from AD shown not only an increase of post-translational modifications TDP-43, such hyperphosphorylation and fragmentation, but also its prionic behaviour cell-to-cell transmission. With the main goal to advance therapeutic interventions, we present this work different kinase inhibitors with potential restore pathological mechanism. Methodology We used healthy controls severe evaluate correction pathology after treatment previously synthetized TTBK1 CK1 inhibitors. Moreover conditioned mediums these cells perform propagation experiments. Results observed lymphoblasts reduced (decreasing phosphorylation increasing nuclear localisation), Furthermore, significant phosphorylation, cytoplasmic accumulation aberrant F-actin protrusions (TNT-like structures) control growing CM were abolished when treated reported used. In addition, cytosolic transport mediated by molecular motors receptor was altered induced pathology, it produced abovementioned pretreated CMs. Conclusion inhibitors, specially VNG1.47 IGS2.7 compounds, avoid patients, being excellent candidates for future therapy prevalent devastating disease.