FUNCTIONAL RESCUE OF TAUOPATHY PHENOTYPES USING TAU RNA REPROGRAMMING IN VIVO

ALVAREZ, RODRIGO; BELFORTE, JUAN E; DAMIANICH, ANA; GALLO, JEAN-MARC; AVALE, M. ELENA; ESPINDOLA, SONIA; SARTOR, MANUELA; FERRARIO, JUAN E

BUENOS AIRES

Congreso; 2do. Congreso de la Federación de Sociedades de Neurociencias de Latinoamérica y el Caribe (FALAN); 2016

Federation of Latin American and Caribbean Neuroscience Societies (FALAN)

Tau is a microtubule-associated protein expressed in neurons, involved in many cellular functions such as microtubule stabilization and axonal transport. Several neurodegenerative diseases (tauopathies) are characterized by the abnormal presence of insoluble forms hyperphoshorilated of tau and aggregated in tangles. Tau is encoded by the MAPT gene, on which exon 10 (E10) can be alternatively spliced, giving rise to Tau isoforms with three (3R) or four (4R) repeats of microtubule binding domains. Both isoforms are expressed in equal amounts in the normal adult human brain. Some tauopathies are associated with an imbalance between the Tau isoforms due to mis-splicing of tau primary transcript, thus, correction of such imbalance might represent a therapeutical approach for those pathologies. In this work we aimed to rescue tauopathy-like phenotypes of mice carrying a human MAPT transgene (hTau mice) which display an excess of 3R Tau. We used a trans-splicing strategy to modulate the inclusion of E10 in the endogenous Tau transcript, via lentiviral vectors injected in the prefrontal cortex (PFC) of htau mice. A significant shift from 3R to 4R isoforms at the RNA and protein level was observed in the injected area. Six months after the trans-splicing therapy the content of insoluble Tau and the number of neurons showing hyperphosphorilated Tau staining were reduced in the PFC. Also neuronal firing of prefrontal neurons of injected hTtau mice were restored to normal levels. Cognitive performance in the NOR task also improved in aged hTau mice after Tau RNA reprogramming. Our results indicate that modulating the splicing of E10 in the tau transcript is sufficient to achieve a relevant phenotypic recovery in the hTau model of tauopathy, raising promising perspectives about RNA reprogramming therapies to treat human neurodegenerative diseases related to tau isoforms imbalance.