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An In Vitro Model for Studying Tau Aggregation Using Lentiviral-mediated Transduction of Human Neurons
Published on: May 23, 2019
Context-dependent toxicity of human tau isoforms in a Drosophila tauopathy model
Yelena Ivanova1, Miguel Ramirez-Moreno2, Jie Liu3
1School of Environmental and Natural Sciences, Bangor University, Bangor LL57 2UR, UK.
Abstract:
Tauopathies are characterised by progressive deterioration of brain regions due to abnormal accumulation of microtubule-associated protein tau (MAPT). Alternative splicing of MAPT pre-mRNA produces six isoforms, classified as 3R or 4R depending on whether they contain three or four microtubule-binding repeats. Although many tauopathies are 3R or 4R specific, individual isoform contributions to neurotoxicity remain unclear. To investigate isoform-specific toxicity, we generated Drosophila lines with transgenes encoding each human tau (hTau) isoform inserted at the same locus. In young adults, hTau abundance did not differ significantly among lines, yet expression levels were sufficient to induce visible, isoform-specific phenotypes. Across assays, hTau toxicity depended on expression window, tissue type, and neuronal identity; 4R isoforms were generally more toxic than 3R isoforms, but individual isoform effects differed by context. In selected neuronal populations, neurons classed as vulnerable showed early degeneration and continued decline, whereas resilient neurons degenerated only at the later time point. This suggests that, in some neurons, resilience may reflect early resistance to disease processes that is lost with age and exposure to age-related stressors. These phenotypes were not readily explained by hTau abundance or AT8-positive hTau. Together, we show that tau toxicity emerges from interactions between isoform-specific properties and cellular environment.
Insights
The toxicity of tau protein in tauopathies depends on specific isoforms and the cellular environment. Researchers found that 4R tau isoforms are generally more toxic than 3R, but context matters.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Tauopathies involve abnormal accumulation of microtubule-associated protein tau (MAPT).
- MAPT pre-mRNA splicing produces six tau isoforms (3R and 4R), but their individual neurotoxic contributions are unclear.
Purpose of the Study:
- To investigate the isoform-specific toxicity of human tau (hTau) in a model organism.
- To understand how cellular environment and neuronal identity influence tau-induced neurotoxicity.
Main Methods:
- Generated Drosophila lines expressing each of the six human tau isoforms at the same genetic locus.
- Assessed tau toxicity through various assays, considering expression window, tissue type, and neuronal identity.
- Examined phenotypes in relation to hTau abundance and AT8-positive hTau levels.
Main Results:
- Expression of hTau isoforms induced visible, isoform-specific phenotypes in young adult Drosophila.
- Generally, 4R tau isoforms exhibited greater toxicity than 3R isoforms, with context-dependent variations.
- Neuronal vulnerability and resilience were observed, suggesting age-related loss of resistance in some neurons.
- Phenotypes were not solely explained by hTau abundance or AT8-positive tau.
Conclusions:
- Tau toxicity is a complex interplay between tau isoform-specific properties and the cellular environment.
- Neuronal resilience may diminish with age and exposure to stressors, contributing to disease progression.
- This study provides insights into the differential neurotoxicity of tau isoforms in tauopathies.
