Several studies have identified multiple physiological functions of Tau at the postsynaptic compartment and in the nucleus, as well as interactions with mitochondria, the plasma membrane and the Actin cytoskeleton. Tau is primarily distributed in axons of the central nervous system (CNS) where it plays major roles in the regulation of microtubule dynamics and axonal transport. Tauopathies encompass a range of neurodegenerative disorders including Pick’s disease (PiD) and Frontotemporal Dementia (FTD), presenting varying clinical symptoms depending on the type of lesion, cell type and affected brain region. In Alzheimer’s disease (AD) and related Tauopathies, aggregation of abnormally phosphorylated Tau protein is considered central to disease pathogenesis. Our work provides mechanistic insights into the role of the Tau cysteine residues as redox-switches regulating the process of Tau self-assembly into inclusions in vivo, its function as a cytoskeletal protein and its effect on neuronal toxicity and dysfunction. Importantly, we also validate results from the fly model in human Tauopathy samples by showing that MICAL1 is up-regulated in patient brains and co-localizes with Tau in Pick bodies. The collective evidence strongly indicates that Mical’s redox activity mediates the effects on Tau via oxidation of Cys322. Exploration of the mechanism was pursued using a Mical inhibitor, a mutation in Mical that selectively disrupts its monooxygenase domain, Tau transgenes mutated at cysteine residues targeted by Mical and mass spectrometry analysis to quantify cysteine oxidation. In the well-established Drosophila Tauopathy model, we use genetic interactions to show that Mical alters Tau interactions with microtubules and the Actin cytoskeleton and greatly affects Tau aggregation propensity and Tau-associated toxicity and dysfunction. Mical is characterized by the presence of a flavoprotein monooxygenase domain that generates redox potential with which it can oxidize target proteins. Mical emerged as a novel interacting protein of human Tau expressed in Drosophila brains. However, processes leading to Tau fibrillization and reasons for its pathogenicity remain largely elusive. PMID: 35835913 PMCID: PMC9355882.Tau accumulation is clearly linked to pathogenesis in Alzheimer’s disease and other Tauopathies. Banday AR, Stanifer ML, Florez-Vargas O, Onabajo OO, Papenberg BW, Zahoor MA, Mirabello L, Ring TJ, Lee CH, Albert PS, Andreakos E, Arons E, Barsh G, Biesecker LG, Boyle DL, Brahier MS, Burnett-Hartman A, Carrington M, Chang E, Choe PG, Chisholm RL, Colli LM, Dalgard CL, Dude CM, Edberg J, Erdmann N, Feigelson HS, Fonseca BA, Firestein GS, Gehring AJ, Guo C, Ho M, Holland S, Hutchinson AA, Im H, Irby L, Ison MG, Joseph NT, Kim HB, Kreitman RJ, Korf BR, Lipkin SM, Mahgoub SM, Mohammed I, Paschoalini GL, Pacheco JA, Peluso MJ, Rader DJ, Redden DT, Ritchie MD, Rosenblum B, Ross ME, Anna HPS, Savage SA, Sharma S, Siouti E, Smith AK, Triantafyllia V, Vargas JM, Vargas JD, Verma A, Vij V, Wesemann DR, Yeager M, Yu X, Zhang Y, Boulant S, Chanock SJ, Feld JJ, Prokunina-Olsson L. Genetic regulation of OAS1 nonsense-mediated decay underlies association with COVID-19 hospitalization in patients of European and African ancestries.
0 Comments
Leave a Reply. |