Repositorio Dspace

SMaRT modulation of tau isoforms rescues cognitive and motor impairments in a preclinical model of tauopathy

Mostrar el registro sencillo del ítem

dc.contributor.author Muñiz, Javier Andrés
dc.contributor.author Facal, Carolina Lucía
dc.contributor.author Urrutia, Leandro
dc.contributor.author Clerici Delville, Ramiro
dc.contributor.author Damianich, Ana
dc.contributor.author Ferrario, Juan Esteban
dc.contributor.author Falasco, Germán
dc.contributor.author Avale, María Elena
dc.date.accessioned 2022-11-23T13:55:29Z
dc.date.available 2022-11-23T13:55:29Z
dc.date.issued 2022-09-05
dc.identifier.citation Muñiz JA, Facal CL, Urrutia L, Clerici-Delville R, Damianich A, Ferrario JE, Falasco G, Avale ME. SMaRT modulation of tau isoforms rescues cognitive and motor impairments in a preclinical model of tauopathy. Front Bioeng Biotechnol. 2022 Oct 5;10:951384. doi: 10.3389/fbioe.2022.951384. es_ES
dc.identifier.uri https://doi.org/10.3389/fbioe.2022.951384
dc.identifier.uri https://repositorio.fleni.org.ar/xmlui/handle/123456789/721
dc.description.abstract Tau is a microtubule-associated protein predominantly expressed in neurons, which participates in microtubule polymerization and axonal transport. Abnormal tau metabolism leads to neurodegenerative diseases named tauopathies, such as Alzheimer's disease and frontotemporal dementia. The alternative splicing of exon 10 (E10) in the primary transcript produces tau protein isoforms with three (3R) or four (4R) microtubule binding repeats, which are found in equal amounts in the normal adult human brain. Several tauopathies are associated with abnormal E10 alternative splicing, leading to an imbalance between 3R and 4R isoforms, which underlies disease. Correction of such imbalance represents a potential disease-modifying therapy for those tauopathies. We have previously optimized a trans-splicing RNA reprogramming strategy to modulate the 3R:4R tau content in a mouse model of tauopathy related to tau mis-splicing (htau mice), and showed that local modulation of E10 inclusion in the prefrontal cortex prevents cognitive decline, neuronal firing impairments and hyperphosphorylated tau accumulation. Furthermore, local shifting of 3R-4R tau into the striatum of htau mice prevented motor coordination deficits. However, a major bottleneck of our previous work is that local splicing regulation was performed in young mice, before the onset of pathological phenotypes. Here we tested whether regulation of tau E10 splicing could rescue tau pathology phenotypes in htau mice, after the onset of cognitive and motor impairments, comparable to early stages of human tauopathies. To determine phenotypic time course and affected brain nuclei, we assessed htau mice using behavioural tests and microPET FDG imaging over time, similarly to diagnosis methods used in patients. Based on these analyses, we performed local delivery of pre-trans splicing molecules to regulate E10 inclusion either into the medial prefrontal cortex (mPFC) or the striatum at 6-month-old once behavioral phenotypes and metabolic changes were detected. Tau isoforms modulation into the mPFC restored cognitive performance in mice that previously showed mild to severe memory impairment while motor coordination deficit was rescued after striatal injection of trans-splicing molecules. Our data suggest that tau regulation could recover pathological phenotypes early after phenotypic onset, raising promising perspectives for the use of RNA based therapies in tauopathies related to MAPT abnormal splicing. es_ES
dc.language.iso eng es_ES
dc.publisher Frontiers Media S.A. es_ES
dc.rights info:eu-repo/semantics/openAccess
dc.rights.uri https://creativecommons.org/licenses/by/2.5/ar/
dc.subject Tauopathies es_ES
dc.subject Tauopatías es_ES
dc.subject tau Proteins es_ES
dc.subject Proteínas tau es_ES
dc.subject Dementia es_ES
dc.subject Demencia es_ES
dc.subject Bioengineering
dc.subject Bioingeniería
dc.title SMaRT modulation of tau isoforms rescues cognitive and motor impairments in a preclinical model of tauopathy es_ES
dc.type info:eu-repo/semantics/article es_ES
dc.type info:ar-repo/semantics/artículo es_ES
dc.type info:eu-repo/semantics/publishedVersion
dc.description.fil Fil: Muñiz, Javier Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina.
dc.description.fil Fil: Facal, Carolina Lucía. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina.
dc.description.fil Fil: Urrutia, Leandro. Fleni. Departamento de Diagnóstico por Imágenes. Centro de Imágenes Moleculares. Laboratorio De Imágenes Preclínicas; Argentina.
dc.description.fil Fil: Clerici-Delville, Ramiro. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina. Instituto de Biociencias, Biotecnología y Biología traslacional. Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires; Argentina.
dc.description.fil Fil: Damianich, Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina.
dc.description.fil Fil: Ferrario, Juan Esteban. Instituto de Biociencias, Biotecnología y Biología traslacional. Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires; Argentina.
dc.description.fil Fil: Falasco, German. Fleni. Departamento de Diagnóstico por Imágenes. Centro de Imágenes Moleculares. Laboratorio De Imágenes Preclínicas; Argentina.
dc.description.fil Fil: Avale, María Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina.
dc.relation.ispartofVOLUME 10
dc.relation.ispartofPAGINATION 951384
dc.relation.ispartofCOUNTRY Suiza
dc.relation.ispartofCITY Lausanne
dc.relation.ispartofTITLE Frontiers in bioengineering and biotechnology
dc.relation.ispartofISSN 2296-4185
dc.type.snrd info:ar-repo/semantics/artículo es_ES


Ficheros en el ítem

Este ítem aparece en la(s) siguiente(s) colección(ones)

Mostrar el registro sencillo del ítem

info:eu-repo/semantics/openAccess Excepto si se señala otra cosa, la licencia del ítem se describe como info:eu-repo/semantics/openAccess

Buscar en DSpace


Listar

Mi cuenta

Estadísticas