MODULATION OF TAU ISOFORMS BY RNA REPROGRAMMING: ANALYSIS OF PHENOTYPIC RESCUE IN A MOUSE MODEL OF TAUOPATHY

SONIA ESPINDOLA; ANA DAMIANICH; ZOE BLANCK; GALLO, JEAN-MARC; AVALE, MARIA ELENA

Congreso; 9th World CongressIBRO2015; 2015

International Brain Research Organization

Tauopathies are major neurodegenerative diseases characterized by the presence of intraneuronal aggregates of the protein tau in insoluble neurofibrillary tangles. Tau is a microtubule-associated protein predominantly expressed in neurons and involved in many 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. The alternative splicing of exon 10 (E10) produces tau isoforms with three (3R) or four (4R) microtubule binding repeats; both isoforms are expressed in equal amounts in the normal adult human brain. Several tauopathies are associated with mutations in the MAPT gene which interfere with E10 alternative splicing, thus altering the normal ratio of Tau 3R/4R=1.Here we analysed a transgenic mouse model that carries a human Tau transgene in a murine mapt -/- background (hTau mice). Htau mice are proposed as a model of tauopathy because they present deposits of hyperphosphorylated Tau in the brain, neurodegeneration and cognitive deficits, from 9 months old. In certain areas of the htau adult brain the content of 3R Tau isoform is higher than the 4R, thus leading to a ratio 3R/4R >1. We investigated if restoring the balance between 3R and 4R Tau isoforms in those areas could produce a phenotypic rescue in htau mice. We performed in vivo RNA reprogramming through a trans-splicing reaction between the Tau endogenous transcript and the RNA of a pre-trans-splicing molecule (PTM) containing Tau E10 to E13. This reaction creates a full length Tau chimeric RNA containing E10 (3R). PTMs were delivered by lentiviral vectors into the brain of three months-old mice. Cognitive performance was tested four to six months after injection using the novel object recognition task (NOR) and the Morris Water Maze. Tau isoforms content was determined by qPCR in the prefrontal cortex, the hippocampus, striatum and substantia nigra pars compacta. Htau mice rescued by trans-splicing showed a decrease in the 3R/4R imbalance in the PTM injected area. Rescued mice did not show the deficit in the NOR task present in control htau mice, indicating that partial restoration of Tau isoforms balance could prevent, or slow, cognitive decline in this model.