Functional rescue of tauopathy phenotypes using Tau RNA reprogramming in vivo

ESPINDOLA, SONIA L.; DAMIANICH, ANA; AVALE, MARÍA ELENA

Buenos Aires

Congreso; 2nd FALAN Congress; 2016

Society for Neuroscience

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 involved in many neuronal processes, such as microtubule polymerization and stabilization, neurite outgrowth and axonal transport. Human TAU is encoded by the MAPT gene, which comprises 16 exons. Exon 10 can be alternatively spliced, giving rise to TAU isoforms with either three (3R) or four (4R) repeats of microtubule binding domains. Both isoforms are expressed in equal amounts in the normal adult human brain. However, several tauopathies are associated with mutations in the MAPT gene which modify E10 alternative splicing, leading to an imbalance between the 3R and 4R isoforms, disrupting the normal 3R/4R=1 ratio. Correction of that imbalance between TAU isoforms might represent a therapeutical approach for those tauopathies. We analyze how restoring the balance of TAU isoforms in the prefrontal cortex using a trans-splicing strategy in a mouse model of tauopathy rescues some of its behavioral and neurochemical phenotypes. 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.