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Tau Lysine Pseudomethylation Regulates Microtubule Binding and Enhances Prion-like Tau Aggregation
Yuxing Xia1,2,3, Brach M Bell1,2,3, Benoit I Giasson1,2,3
1Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
Abstract:
Alzheimer's disease (AD) and frontotemporal dementia (FTD) can be classified as tauopathies, which are a group of neurodegenerative diseases that develop toxic tau aggregates in specific brain regions. These pathological tau inclusions are altered by various post-translational modifications (PTMs) that include phosphorylation, acetylation, and methylation. Tau methylation has emerged as a target of interest for its potential involvement in tau pathomechanisms. Filamentous tau aggregates isolated from patients with AD are methylated at multiple lysine residues, although the exact methyltransferases have not been identified. One strategy to study the site-specific effects of methylation is to create methylation mimetics using a KFC model, which replaces lysine (K) with a hydrophobic group such as phenylalanine (F) to approximate the effects of lysine methylation (C or methyl group). In this study, tau methylmimetics were used to model several functional aspects of tau methylation such as effects on microtubule binding and tau aggregation in cell models. Overall, several tau methylmimetics displayed impaired microtubule binding, and tau methylmimetics enhanced prion-like seeded aggregation in the context of the FTD tau mutation P301L. Like other PTMs, tau methylation is a contributing factor to tau pathogenesis and could be a potential therapeutic drug target for the treatment of different tauopathies.
Insights
Tau methylation, a key modification in neurodegenerative tauopathies like Alzheimer's disease, impacts protein function. Mimicking this modification revealed impaired microtubule binding and enhanced aggregation, suggesting it as a therapeutic target.
Area of Science:
- Neuroscience
- Biochemistry
- Cell Biology
Background:
- Alzheimer's disease (AD) and frontotemporal dementia (FTD) are tauopathies characterized by toxic tau aggregates.
- Post-translational modifications (PTMs), including methylation, alter pathological tau inclusions.
- Tau methylation is implicated in tau pathomechanisms and is found in AD patient aggregates.
Purpose of the Study:
- To investigate the functional consequences of tau methylation in neurodegenerative diseases.
- To model the effects of tau methylation using lysine (K) to phenylalanine (F) (KFC) methylmimetics.
- To explore tau methylation as a potential therapeutic target for tauopathies.
Main Methods:
- Creation of tau methylmimetics using the KFC model to mimic lysine methylation.
- Utilizing cell models to assess the functional impact of tau methylmimetics.
- Evaluating effects on microtubule binding and prion-like seeded tau aggregation.
Main Results:
- Several tau methylmimetics demonstrated impaired microtubule binding.
- Tau methylmimetics promoted prion-like seeded aggregation, particularly with the FTD tau mutation P301L.
- These findings highlight the role of tau methylation in tau pathogenesis.
Conclusions:
- Tau methylation is a significant contributor to tau pathogenesis in neurodegenerative diseases.
- Tau methylmimetics provide a valuable tool for studying methylation's functional effects.
- Targeting tau methylation presents a potential therapeutic strategy for tauopathies.
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