Seminario INGEBI

Tau mis-splicing, motor impairments and striatal dysfunction in a model of tauopathy

Lunes 31 de Mayo

Dra. María Elena Avale

INGEBI CONICET

Tau is a microtubule-associated protein predominantly expressed in neurons, which participates in microtubule polymerization and axonal transport. Abnormal tau metabolism leads to neurodegenerative diseases named tauopathies, such as Alzheimer’s disease and frontotemporal dementia. The alternative splicing of exon 10 (E10) in the Tau transcript produces protein isoforms with three (3R) or four (4R) microtubule binding repeats, which are expressed in equal amounts in the normal adult human brain. Several tauopathies are associated with mutations affecting exon 10 alternative splicing, leading to an imbalance between 3R and 4R isoforms. Correction of that imbalance represent a potential therapeutical approach for those tauopathies. In this talk I will present our recent findings using a trans-splicing RNA reprogramming strategy to modulate the 3R:4R tau ratio in cultured post-mitotic human neurons and the mouse brain by using lentiviral vectors that modulate the ratio of E10 inclusion/exclusion. Together, our results evidence the dysfunctional consequences of tau isoforms imbalance and highlight the potential of using of RNA reprogramming to correct tau mis-splicing in human tauopathies.