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Updated: Sep 28, 2025
In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
Published on: January 2, 2015
Mical modulates Tau toxicity via cysteine oxidation in vivo
Engie Prifti1,2, Eleni N Tsakiri1, Ergina Vourkou1
1Institute for Fundamental Biomedical Research, Biomedical Sciences Research Centre "Alexander Fleming", 34 Fleming Street, 16672, Vari, Greece.
Abstract:
Tau 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.
Insights
Mical protein oxidation of Tau at Cys322 drives Tau aggregation and neurotoxicity in Tauopathies. This redox switch mechanism, identified in Drosophila and validated in human samples, reveals new therapeutic targets for Alzheimer's disease.
Area of Science:
- Neuroscience
- Biochemistry
- Cell Biology
Background:
- Tau protein accumulation is a hallmark of Alzheimer's disease and other tauopathies, but the mechanisms driving its aggregation and pathogenicity are not fully understood.
- Mical, a flavoprotein monooxygenase, interacts with human Tau and possesses redox activity capable of oxidizing target proteins.
Purpose of the Study:
- To investigate the role of Mical in Tau pathogenesis using a Drosophila Tauopathy model.
- To elucidate the molecular mechanisms by which Mical affects Tau aggregation, toxicity, and cytoskeletal interactions.
Main Methods:
- Utilized a Drosophila Tauopathy model with genetic interactions to study Mical-Tau relationships.
- Employed Mical inhibitors, mutated Mical and Tau proteins, and mass spectrometry to analyze Mical's redox activity and its impact on Tau cysteine oxidation.
- Validated findings in human tauopathy brain samples.
Main Results:
- Mical significantly alters Tau interactions with microtubules and the actin cytoskeleton, affecting Tau aggregation and neurotoxicity.
- Mical's redox activity mediates these effects through the oxidation of Tau at Cys322.
- MICAL1 is upregulated and co-localizes with Tau in human tauopathy patient brains.
Conclusions:
- Mical acts as a redox regulator of Tau self-assembly and function via Cys322 oxidation.
- This mechanism contributes to Tau inclusion formation, cytoskeletal dysfunction, and neurotoxicity in tauopathies.
- Identified Mical-mediated Tau oxidation as a potential therapeutic target for Alzheimer's disease and related disorders.
