Cytoplasmic TDP-43 leads to early functional impairments without neurodegeneration in a Serotonergic Neuron-Specific C. elegans Model

Autores
Lacour, Ailin; Vassallu, Florencia; Romussi, Stéfano; Rayes, Diego Hernán; Muller Igaz, Lionel
Año de publicación
2026
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
TDP-43 proteinopathies, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are marked by the pathological cytoplasmic accumulation of TAR DNA-binding protein 43 (TDP-43), leading to progressive neuronal dysfunction and degeneration. To investigate the early functional consequences of TDP-43 mislocalization, we generated Caenorhabditis elegans models expressing either wild-type human TDP-43 or a variant with a mutated nuclear localization signal (ΔNLS), specifically in serotonergic neurons. These neurons were chosen because in C. elegans they regulate well-characterized behaviors, providing a straightforward readout of neuronal function. We found that expression of either TDP-43 variant impaired serotonin-dependent behaviors—including pharyngeal pumping, egg-laying, and locomotion slowing upon food encounter—with the cytoplasmic ΔNLS form causing more severe deficits. These behavioral impairments are evident even while the serotonergic neurons remain apparently normal in structure, suggesting that neuronal dysfunction precedes overt neurodegeneration. Moreover, the serotonergic HSN neurons that control egg-laying were also partially responsive to the selective serotonin reuptake inhibitor fluoxetine, suggesting that neurotransmitter release remains functional to some extent. Altogether, our findings demonstrate that TDP-43 expression causes neuronal dysfunction leading to behavioral deficits, even in the absence of detectable structural pathology and that its mislocalization to the cytoplasm results in more severe behavioral impairments. This C. elegans model provides a genetically tractable system to dissect early mechanisms of TDP-43-mediated neuronal dysfunction and to identify therapeutic strategies targeting predegenerative stages of ALS/FTD
Fil: Lacour, Ailin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Fil: Vassallu, Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina
Fil: Romussi, Stéfano. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Fil: Rayes, Diego Hernán. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Fil: Muller Igaz, Lionel. Universidad de Buenos Aires, Facultad de Ciencias Médicas, Departamento de Ciencias Fisiológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina
Materia
C. ELEGANS
TDP-43
NEURODEGENERATION
PROTEINOPATHIES
SEROTONERGIC NEURONS
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
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oai:ri.conicet.gov.ar:11336/281186
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spelling Cytoplasmic TDP-43 leads to early functional impairments without neurodegeneration in a Serotonergic Neuron-Specific C. elegans ModelLacour, AilinVassallu, FlorenciaRomussi, StéfanoRayes, Diego HernánMuller Igaz, LionelC. ELEGANSTDP-43NEURODEGENERATIONPROTEINOPATHIESSEROTONERGIC NEURONShttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1TDP-43 proteinopathies, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are marked by the pathological cytoplasmic accumulation of TAR DNA-binding protein 43 (TDP-43), leading to progressive neuronal dysfunction and degeneration. To investigate the early functional consequences of TDP-43 mislocalization, we generated Caenorhabditis elegans models expressing either wild-type human TDP-43 or a variant with a mutated nuclear localization signal (ΔNLS), specifically in serotonergic neurons. These neurons were chosen because in C. elegans they regulate well-characterized behaviors, providing a straightforward readout of neuronal function. We found that expression of either TDP-43 variant impaired serotonin-dependent behaviors—including pharyngeal pumping, egg-laying, and locomotion slowing upon food encounter—with the cytoplasmic ΔNLS form causing more severe deficits. These behavioral impairments are evident even while the serotonergic neurons remain apparently normal in structure, suggesting that neuronal dysfunction precedes overt neurodegeneration. Moreover, the serotonergic HSN neurons that control egg-laying were also partially responsive to the selective serotonin reuptake inhibitor fluoxetine, suggesting that neurotransmitter release remains functional to some extent. Altogether, our findings demonstrate that TDP-43 expression causes neuronal dysfunction leading to behavioral deficits, even in the absence of detectable structural pathology and that its mislocalization to the cytoplasm results in more severe behavioral impairments. This C. elegans model provides a genetically tractable system to dissect early mechanisms of TDP-43-mediated neuronal dysfunction and to identify therapeutic strategies targeting predegenerative stages of ALS/FTDFil: Lacour, Ailin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Vassallu, Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Romussi, Stéfano. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Rayes, Diego Hernán. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Muller Igaz, Lionel. Universidad de Buenos Aires, Facultad de Ciencias Médicas, Departamento de Ciencias Fisiológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaSpringer Nature Limited2026-01-23info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/281186Lacour, Ailin; Vassallu, Florencia; Romussi, Stéfano; Rayes, Diego Hernán; Muller Igaz, Lionel; Cytoplasmic TDP-43 leads to early functional impairments without neurodegeneration in a Serotonergic Neuron-Specific C. elegans Model; Springer Nature Limited; Nature Scientific Reports; 23-1-2026; 1-222045-2322CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s41598-026-36138-5info:eu-repo/semantics/altIdentifier/doi/10.1038/s41598-026-36138-5info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2026-02-26T10:22:56Zoai:ri.conicet.gov.ar:11336/281186instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982026-02-26 10:22:56.928CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Cytoplasmic TDP-43 leads to early functional impairments without neurodegeneration in a Serotonergic Neuron-Specific C. elegans Model
title Cytoplasmic TDP-43 leads to early functional impairments without neurodegeneration in a Serotonergic Neuron-Specific C. elegans Model
spellingShingle Cytoplasmic TDP-43 leads to early functional impairments without neurodegeneration in a Serotonergic Neuron-Specific C. elegans Model
Lacour, Ailin
C. ELEGANS
TDP-43
NEURODEGENERATION
PROTEINOPATHIES
SEROTONERGIC NEURONS
title_short Cytoplasmic TDP-43 leads to early functional impairments without neurodegeneration in a Serotonergic Neuron-Specific C. elegans Model
title_full Cytoplasmic TDP-43 leads to early functional impairments without neurodegeneration in a Serotonergic Neuron-Specific C. elegans Model
title_fullStr Cytoplasmic TDP-43 leads to early functional impairments without neurodegeneration in a Serotonergic Neuron-Specific C. elegans Model
title_full_unstemmed Cytoplasmic TDP-43 leads to early functional impairments without neurodegeneration in a Serotonergic Neuron-Specific C. elegans Model
title_sort Cytoplasmic TDP-43 leads to early functional impairments without neurodegeneration in a Serotonergic Neuron-Specific C. elegans Model
dc.creator.none.fl_str_mv Lacour, Ailin
Vassallu, Florencia
Romussi, Stéfano
Rayes, Diego Hernán
Muller Igaz, Lionel
author Lacour, Ailin
author_facet Lacour, Ailin
Vassallu, Florencia
Romussi, Stéfano
Rayes, Diego Hernán
Muller Igaz, Lionel
author_role author
author2 Vassallu, Florencia
Romussi, Stéfano
Rayes, Diego Hernán
Muller Igaz, Lionel
author2_role author
author
author
author
dc.subject.none.fl_str_mv C. ELEGANS
TDP-43
NEURODEGENERATION
PROTEINOPATHIES
SEROTONERGIC NEURONS
topic C. ELEGANS
TDP-43
NEURODEGENERATION
PROTEINOPATHIES
SEROTONERGIC NEURONS
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv TDP-43 proteinopathies, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are marked by the pathological cytoplasmic accumulation of TAR DNA-binding protein 43 (TDP-43), leading to progressive neuronal dysfunction and degeneration. To investigate the early functional consequences of TDP-43 mislocalization, we generated Caenorhabditis elegans models expressing either wild-type human TDP-43 or a variant with a mutated nuclear localization signal (ΔNLS), specifically in serotonergic neurons. These neurons were chosen because in C. elegans they regulate well-characterized behaviors, providing a straightforward readout of neuronal function. We found that expression of either TDP-43 variant impaired serotonin-dependent behaviors—including pharyngeal pumping, egg-laying, and locomotion slowing upon food encounter—with the cytoplasmic ΔNLS form causing more severe deficits. These behavioral impairments are evident even while the serotonergic neurons remain apparently normal in structure, suggesting that neuronal dysfunction precedes overt neurodegeneration. Moreover, the serotonergic HSN neurons that control egg-laying were also partially responsive to the selective serotonin reuptake inhibitor fluoxetine, suggesting that neurotransmitter release remains functional to some extent. Altogether, our findings demonstrate that TDP-43 expression causes neuronal dysfunction leading to behavioral deficits, even in the absence of detectable structural pathology and that its mislocalization to the cytoplasm results in more severe behavioral impairments. This C. elegans model provides a genetically tractable system to dissect early mechanisms of TDP-43-mediated neuronal dysfunction and to identify therapeutic strategies targeting predegenerative stages of ALS/FTD
Fil: Lacour, Ailin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Fil: Vassallu, Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina
Fil: Romussi, Stéfano. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Fil: Rayes, Diego Hernán. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Fil: Muller Igaz, Lionel. Universidad de Buenos Aires, Facultad de Ciencias Médicas, Departamento de Ciencias Fisiológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina
description TDP-43 proteinopathies, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are marked by the pathological cytoplasmic accumulation of TAR DNA-binding protein 43 (TDP-43), leading to progressive neuronal dysfunction and degeneration. To investigate the early functional consequences of TDP-43 mislocalization, we generated Caenorhabditis elegans models expressing either wild-type human TDP-43 or a variant with a mutated nuclear localization signal (ΔNLS), specifically in serotonergic neurons. These neurons were chosen because in C. elegans they regulate well-characterized behaviors, providing a straightforward readout of neuronal function. We found that expression of either TDP-43 variant impaired serotonin-dependent behaviors—including pharyngeal pumping, egg-laying, and locomotion slowing upon food encounter—with the cytoplasmic ΔNLS form causing more severe deficits. These behavioral impairments are evident even while the serotonergic neurons remain apparently normal in structure, suggesting that neuronal dysfunction precedes overt neurodegeneration. Moreover, the serotonergic HSN neurons that control egg-laying were also partially responsive to the selective serotonin reuptake inhibitor fluoxetine, suggesting that neurotransmitter release remains functional to some extent. Altogether, our findings demonstrate that TDP-43 expression causes neuronal dysfunction leading to behavioral deficits, even in the absence of detectable structural pathology and that its mislocalization to the cytoplasm results in more severe behavioral impairments. This C. elegans model provides a genetically tractable system to dissect early mechanisms of TDP-43-mediated neuronal dysfunction and to identify therapeutic strategies targeting predegenerative stages of ALS/FTD
publishDate 2026
dc.date.none.fl_str_mv 2026-01-23
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/281186
Lacour, Ailin; Vassallu, Florencia; Romussi, Stéfano; Rayes, Diego Hernán; Muller Igaz, Lionel; Cytoplasmic TDP-43 leads to early functional impairments without neurodegeneration in a Serotonergic Neuron-Specific C. elegans Model; Springer Nature Limited; Nature Scientific Reports; 23-1-2026; 1-22
2045-2322
CONICET Digital
CONICET
url http://hdl.handle.net/11336/281186
identifier_str_mv Lacour, Ailin; Vassallu, Florencia; Romussi, Stéfano; Rayes, Diego Hernán; Muller Igaz, Lionel; Cytoplasmic TDP-43 leads to early functional impairments without neurodegeneration in a Serotonergic Neuron-Specific C. elegans Model; Springer Nature Limited; Nature Scientific Reports; 23-1-2026; 1-22
2045-2322
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
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info:eu-repo/semantics/altIdentifier/doi/10.1038/s41598-026-36138-5
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
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eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
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dc.publisher.none.fl_str_mv Springer Nature Limited
publisher.none.fl_str_mv Springer Nature Limited
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
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instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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