SMaRT modulation of tau isoforms rescues cognitive and motor impairments in a preclinical model of tauopathy
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 s...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2022-10-01
|
| Series: | Frontiers in Bioengineering and Biotechnology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fbioe.2022.951384/full |
| _version_ | 1797997459080740864 |
|---|---|
| author | Javier Andrés Muñiz Carolina Lucía Facal Leandro Urrutia Ramiro Clerici-Delville Ramiro Clerici-Delville Ana Damianich Juan E. Ferrario Germán Falasco María Elena Avale |
| author_facet | Javier Andrés Muñiz Carolina Lucía Facal Leandro Urrutia Ramiro Clerici-Delville Ramiro Clerici-Delville Ana Damianich Juan E. Ferrario Germán Falasco María Elena Avale |
| author_sort | Javier Andrés Muñiz |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T10:32:13Z |
| format | Article |
| id | doaj.art-36ed0e9e232c4960b582dd1a46c7cdb2 |
| institution | Directory Open Access Journal |
| issn | 2296-4185 |
| language | English |
| last_indexed | 2024-04-11T10:32:13Z |
| publishDate | 2022-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Bioengineering and Biotechnology |
| spelling | doaj.art-36ed0e9e232c4960b582dd1a46c7cdb22022-12-22T04:29:23ZengFrontiers Media S.A.Frontiers in Bioengineering and Biotechnology2296-41852022-10-011010.3389/fbioe.2022.951384951384SMaRT modulation of tau isoforms rescues cognitive and motor impairments in a preclinical model of tauopathyJavier Andrés Muñiz0Carolina Lucía Facal1Leandro Urrutia2Ramiro Clerici-Delville3Ramiro Clerici-Delville4Ana Damianich5Juan E. Ferrario6Germán Falasco7María Elena Avale8Consejo Nacional de Investigaciones Científicas y Técnicas, Instituto de Investigaciones en Ingeniería Genética y Biología Molecular “Dr Héctor N Torres”, Buenos Aires, ArgentinaConsejo Nacional de Investigaciones Científicas y Técnicas, Instituto de Investigaciones en Ingeniería Genética y Biología Molecular “Dr Héctor N Torres”, Buenos Aires, ArgentinaLaboratorio De Imágenes Preclínicas, Centro de Imágenes Moleculares, FLENI, Buenos Aires, ArgentinaConsejo Nacional de Investigaciones Científicas y Técnicas, Instituto de Investigaciones en Ingeniería Genética y Biología Molecular “Dr Héctor N Torres”, Buenos Aires, ArgentinaUniversidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Instituto de Biociencias, Biotecnología y Biología traslacional (iB3), Buenos Aires, ArgentinaConsejo Nacional de Investigaciones Científicas y Técnicas, Instituto de Investigaciones en Ingeniería Genética y Biología Molecular “Dr Héctor N Torres”, Buenos Aires, ArgentinaUniversidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Instituto de Biociencias, Biotecnología y Biología traslacional (iB3), Buenos Aires, ArgentinaLaboratorio De Imágenes Preclínicas, Centro de Imágenes Moleculares, FLENI, Buenos Aires, ArgentinaConsejo Nacional de Investigaciones Científicas y Técnicas, Instituto de Investigaciones en Ingeniería Genética y Biología Molecular “Dr Héctor N Torres”, Buenos Aires, ArgentinaTau 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.https://www.frontiersin.org/articles/10.3389/fbioe.2022.951384/fullMAPTRNA therapyTrans-SplicingDementiaFDG-microPET |
| spellingShingle | Javier Andrés Muñiz Carolina Lucía Facal Leandro Urrutia Ramiro Clerici-Delville Ramiro Clerici-Delville Ana Damianich Juan E. Ferrario Germán Falasco María Elena Avale SMaRT modulation of tau isoforms rescues cognitive and motor impairments in a preclinical model of tauopathy Frontiers in Bioengineering and Biotechnology MAPT RNA therapy Trans-Splicing Dementia FDG-microPET |
| title | SMaRT modulation of tau isoforms rescues cognitive and motor impairments in a preclinical model of tauopathy |
| title_full | SMaRT modulation of tau isoforms rescues cognitive and motor impairments in a preclinical model of tauopathy |
| title_fullStr | SMaRT modulation of tau isoforms rescues cognitive and motor impairments in a preclinical model of tauopathy |
| title_full_unstemmed | SMaRT modulation of tau isoforms rescues cognitive and motor impairments in a preclinical model of tauopathy |
| title_short | SMaRT modulation of tau isoforms rescues cognitive and motor impairments in a preclinical model of tauopathy |
| title_sort | smart modulation of tau isoforms rescues cognitive and motor impairments in a preclinical model of tauopathy |
| topic | MAPT RNA therapy Trans-Splicing Dementia FDG-microPET |
| url | https://www.frontiersin.org/articles/10.3389/fbioe.2022.951384/full |
| work_keys_str_mv | AT javierandresmuniz smartmodulationoftauisoformsrescuescognitiveandmotorimpairmentsinapreclinicalmodeloftauopathy AT carolinaluciafacal smartmodulationoftauisoformsrescuescognitiveandmotorimpairmentsinapreclinicalmodeloftauopathy AT leandrourrutia smartmodulationoftauisoformsrescuescognitiveandmotorimpairmentsinapreclinicalmodeloftauopathy AT ramiroclericidelville smartmodulationoftauisoformsrescuescognitiveandmotorimpairmentsinapreclinicalmodeloftauopathy AT ramiroclericidelville smartmodulationoftauisoformsrescuescognitiveandmotorimpairmentsinapreclinicalmodeloftauopathy AT anadamianich smartmodulationoftauisoformsrescuescognitiveandmotorimpairmentsinapreclinicalmodeloftauopathy AT juaneferrario smartmodulationoftauisoformsrescuescognitiveandmotorimpairmentsinapreclinicalmodeloftauopathy AT germanfalasco smartmodulationoftauisoformsrescuescognitiveandmotorimpairmentsinapreclinicalmodeloftauopathy AT mariaelenaavale smartmodulationoftauisoformsrescuescognitiveandmotorimpairmentsinapreclinicalmodeloftauopathy |