Author: Yang, Taehong ; Srapyan, Sargis ; Baskar, Raju ; Grintsevich, Elena E ; Terman, Jonathan R ; Wu, Heng ; Rajan, Sudeepa ; Ahmed, Giasuddin ; Yoon, Jimok ; Reisler, Emil

Cellular form and function are controlled by the assembly and stability of actin cytoskeletal structures-but disassembling/pruning these structures is equally essential for the plasticity and remodeling that underlie behavioral adaptations. Importantly, the mechanisms of actin assembly have been well-defined-including that it is driven by actin's polymerization into filaments (F-actin) and then often bundling by crosslinking proteins into stable higher-order structures. In contrast, it remains less clear how these stable bundled F-actin structures are rapidly disassembled. We now uncover mechanisms that rapidly and extensively disassemble bundled F-actin. Using biochemical, structural, and imaging assays with purified proteins, we show that F-actin bundled with one of the most prominent crosslinkers, fascin, is extensively disassembled by Mical, the F-actin disassembly enzyme. Furthermore, the product of this Mical effect, Mical-oxidized actin, is poorly bundled by fascin, thereby further amplifying Mical's disassembly effects on bundled F-actin. Moreover, another critical F-actin regulator, cofilin, also affects fascin-bundled filaments, but we find herein that it synergizes with Mical to dramatically amplify its disassembly of bundled F-actin compared to the sum of their individual effects. Genetic and high-resolution cellular assays reveal that Mical also counteracts crosslinking proteins/bundled F-actin in vivo to control cellular extension, axon guidance, and Semaphorin/Plexin cell-cell repulsion. Yet, our results also support the idea that fascin-bundling serves to dampen Mical's F-actin disassembly in vitro and in vivo-and that physiologically relevant cellular remodeling requires a fine-tuned interplay between the factors that build bundled F-actin networks and those that disassemble them.

01 Dec 2022·Acta Neuropathologica Communications

Correction to: Mical modulates Tau toxicity via cysteine oxidation in vivo

Author: Samiotaki, Martina ; Vourkou, Ergina ; Skoulakis, Efthimios M C ; Tsakiri, Eleni N ; Papanikolopoulou, Katerina ; Stamatakis, George ; Prifti, Engie

01 Dec 2022·Acta Neuropathologica CommunicationsQ2 · MEDICINE

Mical modulates Tau toxicity via cysteine oxidation in vivo

Q2 · MEDICINE

ArticleOA

Author: Samiotaki, Martina ; Vourkou, Ergina ; Skoulakis, Efthimios M C ; Tsakiri, Eleni N ; Papanikolopoulou, Katerina ; Prifti, Engie ; Stamatakis, George

AbstractTau accumulation is clearly linked to pathogenesis in Alzheimer’s disease and other Tauopathies. However, processes leading to Tau fibrillization and reasons for its pathogenicity remain largely elusive. Mical emerged as a novel interacting protein of human Tau expressed in Drosophila brains. Mical is characterized by the presence of a flavoprotein monooxygenase domain that generates redox potential with which it can oxidize target proteins. 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. 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. The collective evidence strongly indicates that Mical’s redox activity mediates the effects on Tau via oxidation of Cys322. 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. 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.

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Indication	Highest Phase	Country/Location	Organization	Date
Psoriasis	Phase 3	CA	Crescita Therapeutics, Inc.	23 Sep 2021

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