Dysfunction of the microtubule associated protein TAU in motor and cognitive impairments: a potential molecular therapy for tauopathies

LIC. ANA DAMIANICH; CAROLINA LUCIA FACAL; LIC. SONIA L ESPINDOLA; LIC. MANUELA SARTOR; DR. JUAN E FERRARIO; DRA. MARÍA ELENA AVALE

Capital Federal

Simposio; Fronteras en Biociencia 3; 2018

IBioBA - MPSP

Microtubule-associated protein TAU is expressed in neurons and involved in microtubule polymerization and axonal transport. Tauopathies are neurodegenerative diseases involving abnormal tau metabolism, that leads to the deposition of insoluble aggregates of hyperphosphorilated tau. Human tau is encoded by the MAPT gene, which comprises 16 exons. Exon 10 can be alternatively spliced, giving rise to tau isoforms with three (3R) or four (4R) microtubule binding repeats, both isoforms are expressed in equal amounts in the normal adult human brain. However, several tauopathies such as Progressive Supranuclear Palsy and FTDP-17, are associated with mutations in the MAPT gene that interfere with E10 alternative splicing, leading to an imbalance between the 3R and 4R isoforms and disrupting the normal 3R/4R=1 ratio. Correction of that imbalance between TAU isoforms might represent a therapeutical approach for these tauopathies. In this work, we evaluate cognitive and motor phenotypes in a mouse model of tauopathy: the hTau mice. This model carries a human Tau transgene which produces an excess of 3R Tau, leading to abnormal ratio of Tau isoforms in several brain areas. We sought to correct that Tau isoform imbalance using a trans-splicing strategy (LV-TAU PTMR) and analyze if such restoration produces a phenotypic rescue . Our results indicate that modulating the splicing of E10 in the TAU transcript is sufficient to preclude tauopathy phenotypes in the hTAU model, raising promising perspectives about RNA reprogramming therapies to treat human neurodegenerative diseases related to TAU isoforms imbalance.