Post-transcriptional regulation of the microtubule associated protein TAU: Functional consequences and therapeutic perspectives

MARIA ELENA AVALE; ANA DAMIANICH; CAROLINA FACAL; JAVIER MUÑIZ; SONIA ESPINDOLA

Paris

Conferencia; FENS forum; 2022

Tau is a microtubule-associated protein, predominantly expressed in neurons, that regulates a myriad of neuronalprocesses. Abnormal tau metabolism underly many neurodegenerative diseases, named tauopathies, such asAlzheimer?s disease, frontotemporal dementia and progressive supranuclear palsy. The tau primary transcriptundergoes highly regulated post-transcriptional modifications in the brain; and failures in such processing leads todisease. Particularly, in the normal adult brain, the alternative splicing of exon 10 (E10) produces equal amounts oftau protein isoforms with three (3R) or four (4R) microtubule binding repeats. Several mutations -and also othernon-genetic factors- affecting E10 alternative splicing are associated with tauopathies. Targeting Tau RNAprocessing is therefore a promising avenue to develop effective therapies.In this talk I will outline our achievements using RNA based strategies to modulate either the tau 3R:4R ratio ortotal tau contents, in a mouse model of tauopathy (htau mice). We used lentiviral vectors to express molecules thatmodulate E10 inclusion/exclusion by RNA trans-splicing with the endogenous tau transcript. When delivered intothe prefrontal cortex, these molecules improved cognitive deficit, restored neuronal firing patterns and reducedhyperphosphorylated tau contents. Moreover, shifting of 3R to 4R tau into the striatum rescued motorcoordination deficits.Furthermore, we tested designed microRNAs to locally reduce tau contents in the adult htau brain. Tau knockdownin the htau prefrontal cortex rescued cognitive impairments and pathological phenotypes, even after phenotypiconset.Together, our results evidence the (dys)functional consequences of abnormal tau post-transcriptional regulationand highlight the potential of using RNA-based therapeutic strategies for tauopathies.