CJCADR Research Presentation: Modulating Tau isoforms by RNA reprogramming - Functional consequences and therapeutic perspectives
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- Dr Maria Elena Avale
Institute of Molecular Biology and Genetic Engineering (INGEBI), Laboratory of Experimental Therapeutics for Neurodegenerative Processes, Buenos Aires, Argentina
Title: Modulating Tau isoforms by RNA reprogramming: Functional consequences and therapeutic perspectives
Abstract:
Tau is a microtubule-associated protein predominantly expressed in neurons, which participates in a myriad of cellular functions such as microtubule polymerization and stabilization, neurite outgrowth and axonal transport. Human Tau is encoded by the MAPT gene, which comprises 16 exons. Alternative splicing of exons 2, 3 and 10 gives rise to six tau isoforms in the adult human brain. Particularly, the alternative splicing of exon 10 (E10) produces tau isoforms with either three (3R) or four (4R) microtubule binding repeats. Tau 3R and 4R isoforms are expressed in equal amounts in the normal adult human brain. Tauopathies are major neurodegenerative diseases, characterized by the presence of intraneuronal aggregates of Tau in insoluble neurofibrillary tangles (NFTs). Several tauopathies, such as frontotemporal dementia associated to chromosome 17 (FTDP-17), are associated with mutations in the MAPT gene which interfere with exon 10 alternative splicing, leading to an imbalance between 3R and 4R isoforms, and thus disrupting the normal 3R/4R≈1 ratio. Correction of that imbalance might represent a plausible therapeutic approach for those tauopathies. RNA reprogramming is a promising alternative to this end as it offers several advantages over other strategies: i) It does not alter the total amount of endogenous transcript and ii) the repaired product has the same expression pattern than the normal transcript.
In this talk I will summarise our achievements using an RNA reprogramming strategy to modulate the Tau 3R/4R ratio, either in cultured post mitotic human neurons differentiated in vitro or into the mouse brain. In human neurons we analysed the effect of Tau 3R/4R imbalance on key neuronal properties such as axonal transport. In a mouse model of tauopathy, carrying the human MAPT gene (hTau mice) we modulated the Tau 3R/4R balance and observed a partial rescue on behavioural and neurochemical phenotypes, Including cognitive deficit and content of Tau aggregates in the prefrontal cortex.
Together, our results evidence some of the (dys)functional consequences of Tau 3R/4R imbalance in mature neurons and rise the potential use of RNA reprogramming to correct tau mis-splicing to treat some human tauopathies.
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