TDP-43 proteinopathy in ALS is triggered by loss of ASRGL1 and associated with HML-2 expression
- Autores
- Garcia Montojo, Marta; Fathi, Saeed; Rastegar, Cyrus; Simula, Elena Rita; Doucet O’Hare, Tara; Cheng, Y. H. Hank; Abrams, Rachel P. M.; Pasternack, Nicholas; Malik, Nasir; Bachani, Muzna; Disanza, Brianna; Maric, Dragan; Lee, Myoung Hwa; Wang, Herui; Santamaria, Ulisses; Li, Wenxue; Sampson, Kevon; Lorenzo Lopez, Juan Ramiro; Sánchez Miguel, Ignacio Enrique; Mezghrani, Alexandre; Li, Yan; Sechi, Leonardo Antonio; Pineda, Sebastian; Heiman, Myriam; Kellis, Manolis; Steiner, Joseph; Nath, Avindra
- Año de publicación
- 2024
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- TAR DNA-binding protein 43 (TDP-43) proteinopathy in brain cells is the hallmark of amyotrophic lateral sclerosis (ALS) but its cause remains elusive. Asparaginase-like-1 protein (ASRGL1) cleaves isoaspartates, which alter protein folding and susceptibility to proteolysis. ASRGL1 gene harbors a copy of the human endogenous retrovirus HML-2, whose overexpression contributes to ALS pathogenesis. Here we show that ASRGL1 expression was diminished in ALS brain samples by RNA sequencing, immunohistochemistry, and western blotting. TDP-43 and ASRGL1 colocalized in neurons but, in the absence of ASRGL1, TDP-43 aggregated in the cytoplasm. TDP-43 was found to be prone to isoaspartate formation and a substrate for ASRGL1. ASRGL1 silencing triggered accumulation of misfolded, fragmented, phosphorylated and mislocalized TDP-43 in cultured neurons and motor cortex of female mice. Overexpression of ASRGL1 restored neuronal viability. Overexpression of HML-2 led to ASRGL1 silencing. Loss of ASRGL1 leading to TDP-43 aggregation may be a critical mechanism in ALS pathophysiology.
Fil: Garcia Montojo, Marta. National Institutes of Health; Estados Unidos
Fil: Fathi, Saeed. National Institutes of Health; Estados Unidos
Fil: Rastegar, Cyrus. National Institutes of Health; Estados Unidos
Fil: Simula, Elena Rita. National Institutes of Health; Estados Unidos. Azienda Ospedaliera Universitaria Sassari; Italia
Fil: Doucet O’Hare, Tara. National Institutes of Health; Estados Unidos
Fil: Cheng, Y. H. Hank. National Institutes of Health; Estados Unidos
Fil: Abrams, Rachel P. M.. National Institutes of Health; Estados Unidos
Fil: Pasternack, Nicholas. National Institutes of Health; Estados Unidos
Fil: Malik, Nasir. National Institutes of Health; Estados Unidos
Fil: Bachani, Muzna. National Institutes of Health; Estados Unidos
Fil: Disanza, Brianna. National Institutes of Health; Estados Unidos
Fil: Maric, Dragan. National Institutes of Health; Estados Unidos
Fil: Lee, Myoung Hwa. National Institutes of Health; Estados Unidos
Fil: Wang, Herui. National Institutes of Health; Estados Unidos
Fil: Santamaria, Ulisses. National Institutes of Health; Estados Unidos
Fil: Li, Wenxue. National Institutes of Health; Estados Unidos
Fil: Sampson, Kevon. National Institutes of Health; Estados Unidos
Fil: Lorenzo Lopez, Juan Ramiro. National Institutes of Health; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; Argentina
Fil: Sánchez Miguel, Ignacio Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; Argentina
Fil: Mezghrani, Alexandre. National Institutes of Health; Estados Unidos. Centre National de la Recherche Scientifique; Francia
Fil: Li, Yan. National Institutes of Health; Estados Unidos
Fil: Sechi, Leonardo Antonio. National Institutes of Health; Estados Unidos
Fil: Pineda, Sebastian. National Institutes of Health; Estados Unidos
Fil: Heiman, Myriam. National Institutes of Health; Estados Unidos
Fil: Kellis, Manolis. National Institutes of Health; Estados Unidos
Fil: Steiner, Joseph. National Institutes of Health; Estados Unidos
Fil: Nath, Avindra. National Institutes of Health; Estados Unidos - Materia
-
proteinopathy
deamidation
TDP-43
amyotrophic lateral sclerosis - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
- Repositorio
.jpg)
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/266094
Ver los metadatos del registro completo
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TDP-43 proteinopathy in ALS is triggered by loss of ASRGL1 and associated with HML-2 expressionGarcia Montojo, MartaFathi, SaeedRastegar, CyrusSimula, Elena RitaDoucet O’Hare, TaraCheng, Y. H. HankAbrams, Rachel P. M.Pasternack, NicholasMalik, NasirBachani, MuznaDisanza, BriannaMaric, DraganLee, Myoung HwaWang, HeruiSantamaria, UlissesLi, WenxueSampson, KevonLorenzo Lopez, Juan RamiroSánchez Miguel, Ignacio EnriqueMezghrani, AlexandreLi, YanSechi, Leonardo AntonioPineda, SebastianHeiman, MyriamKellis, ManolisSteiner, JosephNath, AvindraproteinopathydeamidationTDP-43amyotrophic lateral sclerosishttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1TAR DNA-binding protein 43 (TDP-43) proteinopathy in brain cells is the hallmark of amyotrophic lateral sclerosis (ALS) but its cause remains elusive. Asparaginase-like-1 protein (ASRGL1) cleaves isoaspartates, which alter protein folding and susceptibility to proteolysis. ASRGL1 gene harbors a copy of the human endogenous retrovirus HML-2, whose overexpression contributes to ALS pathogenesis. Here we show that ASRGL1 expression was diminished in ALS brain samples by RNA sequencing, immunohistochemistry, and western blotting. TDP-43 and ASRGL1 colocalized in neurons but, in the absence of ASRGL1, TDP-43 aggregated in the cytoplasm. TDP-43 was found to be prone to isoaspartate formation and a substrate for ASRGL1. ASRGL1 silencing triggered accumulation of misfolded, fragmented, phosphorylated and mislocalized TDP-43 in cultured neurons and motor cortex of female mice. Overexpression of ASRGL1 restored neuronal viability. Overexpression of HML-2 led to ASRGL1 silencing. Loss of ASRGL1 leading to TDP-43 aggregation may be a critical mechanism in ALS pathophysiology.Fil: Garcia Montojo, Marta. National Institutes of Health; Estados UnidosFil: Fathi, Saeed. National Institutes of Health; Estados UnidosFil: Rastegar, Cyrus. National Institutes of Health; Estados UnidosFil: Simula, Elena Rita. National Institutes of Health; Estados Unidos. Azienda Ospedaliera Universitaria Sassari; ItaliaFil: Doucet O’Hare, Tara. National Institutes of Health; Estados UnidosFil: Cheng, Y. H. Hank. National Institutes of Health; Estados UnidosFil: Abrams, Rachel P. M.. National Institutes of Health; Estados UnidosFil: Pasternack, Nicholas. National Institutes of Health; Estados UnidosFil: Malik, Nasir. National Institutes of Health; Estados UnidosFil: Bachani, Muzna. National Institutes of Health; Estados UnidosFil: Disanza, Brianna. National Institutes of Health; Estados UnidosFil: Maric, Dragan. National Institutes of Health; Estados UnidosFil: Lee, Myoung Hwa. National Institutes of Health; Estados UnidosFil: Wang, Herui. National Institutes of Health; Estados UnidosFil: Santamaria, Ulisses. National Institutes of Health; Estados UnidosFil: Li, Wenxue. National Institutes of Health; Estados UnidosFil: Sampson, Kevon. National Institutes of Health; Estados UnidosFil: Lorenzo Lopez, Juan Ramiro. National Institutes of Health; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; ArgentinaFil: Sánchez Miguel, Ignacio Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; ArgentinaFil: Mezghrani, Alexandre. National Institutes of Health; Estados Unidos. Centre National de la Recherche Scientifique; FranciaFil: Li, Yan. National Institutes of Health; Estados UnidosFil: Sechi, Leonardo Antonio. National Institutes of Health; Estados UnidosFil: Pineda, Sebastian. National Institutes of Health; Estados UnidosFil: Heiman, Myriam. National Institutes of Health; Estados UnidosFil: Kellis, Manolis. National Institutes of Health; Estados UnidosFil: Steiner, Joseph. National Institutes of Health; Estados UnidosFil: Nath, Avindra. National Institutes of Health; Estados UnidosNature2024-05info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/266094Garcia Montojo, Marta; Fathi, Saeed; Rastegar, Cyrus; Simula, Elena Rita; Doucet O’Hare, Tara; et al.; TDP-43 proteinopathy in ALS is triggered by loss of ASRGL1 and associated with HML-2 expression; Nature; Nature Communications; 15; 1; 5-2024; 1-242041-1723CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1038/s41467-024-48488-7info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s41467-024-48488-7info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-10T13:08:09Zoai:ri.conicet.gov.ar:11336/266094instacron: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:34982025-09-10 13:08:10.197CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
| dc.title.none.fl_str_mv |
TDP-43 proteinopathy in ALS is triggered by loss of ASRGL1 and associated with HML-2 expression |
| title |
TDP-43 proteinopathy in ALS is triggered by loss of ASRGL1 and associated with HML-2 expression |
| spellingShingle |
TDP-43 proteinopathy in ALS is triggered by loss of ASRGL1 and associated with HML-2 expression Garcia Montojo, Marta proteinopathy deamidation TDP-43 amyotrophic lateral sclerosis |
| title_short |
TDP-43 proteinopathy in ALS is triggered by loss of ASRGL1 and associated with HML-2 expression |
| title_full |
TDP-43 proteinopathy in ALS is triggered by loss of ASRGL1 and associated with HML-2 expression |
| title_fullStr |
TDP-43 proteinopathy in ALS is triggered by loss of ASRGL1 and associated with HML-2 expression |
| title_full_unstemmed |
TDP-43 proteinopathy in ALS is triggered by loss of ASRGL1 and associated with HML-2 expression |
| title_sort |
TDP-43 proteinopathy in ALS is triggered by loss of ASRGL1 and associated with HML-2 expression |
| dc.creator.none.fl_str_mv |
Garcia Montojo, Marta Fathi, Saeed Rastegar, Cyrus Simula, Elena Rita Doucet O’Hare, Tara Cheng, Y. H. Hank Abrams, Rachel P. M. Pasternack, Nicholas Malik, Nasir Bachani, Muzna Disanza, Brianna Maric, Dragan Lee, Myoung Hwa Wang, Herui Santamaria, Ulisses Li, Wenxue Sampson, Kevon Lorenzo Lopez, Juan Ramiro Sánchez Miguel, Ignacio Enrique Mezghrani, Alexandre Li, Yan Sechi, Leonardo Antonio Pineda, Sebastian Heiman, Myriam Kellis, Manolis Steiner, Joseph Nath, Avindra |
| author |
Garcia Montojo, Marta |
| author_facet |
Garcia Montojo, Marta Fathi, Saeed Rastegar, Cyrus Simula, Elena Rita Doucet O’Hare, Tara Cheng, Y. H. Hank Abrams, Rachel P. M. Pasternack, Nicholas Malik, Nasir Bachani, Muzna Disanza, Brianna Maric, Dragan Lee, Myoung Hwa Wang, Herui Santamaria, Ulisses Li, Wenxue Sampson, Kevon Lorenzo Lopez, Juan Ramiro Sánchez Miguel, Ignacio Enrique Mezghrani, Alexandre Li, Yan Sechi, Leonardo Antonio Pineda, Sebastian Heiman, Myriam Kellis, Manolis Steiner, Joseph Nath, Avindra |
| author_role |
author |
| author2 |
Fathi, Saeed Rastegar, Cyrus Simula, Elena Rita Doucet O’Hare, Tara Cheng, Y. H. Hank Abrams, Rachel P. M. Pasternack, Nicholas Malik, Nasir Bachani, Muzna Disanza, Brianna Maric, Dragan Lee, Myoung Hwa Wang, Herui Santamaria, Ulisses Li, Wenxue Sampson, Kevon Lorenzo Lopez, Juan Ramiro Sánchez Miguel, Ignacio Enrique Mezghrani, Alexandre Li, Yan Sechi, Leonardo Antonio Pineda, Sebastian Heiman, Myriam Kellis, Manolis Steiner, Joseph Nath, Avindra |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
proteinopathy deamidation TDP-43 amyotrophic lateral sclerosis |
| topic |
proteinopathy deamidation TDP-43 amyotrophic lateral sclerosis |
| purl_subject.fl_str_mv |
https://purl.org/becyt/ford/1.6 https://purl.org/becyt/ford/1 |
| dc.description.none.fl_txt_mv |
TAR DNA-binding protein 43 (TDP-43) proteinopathy in brain cells is the hallmark of amyotrophic lateral sclerosis (ALS) but its cause remains elusive. Asparaginase-like-1 protein (ASRGL1) cleaves isoaspartates, which alter protein folding and susceptibility to proteolysis. ASRGL1 gene harbors a copy of the human endogenous retrovirus HML-2, whose overexpression contributes to ALS pathogenesis. Here we show that ASRGL1 expression was diminished in ALS brain samples by RNA sequencing, immunohistochemistry, and western blotting. TDP-43 and ASRGL1 colocalized in neurons but, in the absence of ASRGL1, TDP-43 aggregated in the cytoplasm. TDP-43 was found to be prone to isoaspartate formation and a substrate for ASRGL1. ASRGL1 silencing triggered accumulation of misfolded, fragmented, phosphorylated and mislocalized TDP-43 in cultured neurons and motor cortex of female mice. Overexpression of ASRGL1 restored neuronal viability. Overexpression of HML-2 led to ASRGL1 silencing. Loss of ASRGL1 leading to TDP-43 aggregation may be a critical mechanism in ALS pathophysiology. Fil: Garcia Montojo, Marta. National Institutes of Health; Estados Unidos Fil: Fathi, Saeed. National Institutes of Health; Estados Unidos Fil: Rastegar, Cyrus. National Institutes of Health; Estados Unidos Fil: Simula, Elena Rita. National Institutes of Health; Estados Unidos. Azienda Ospedaliera Universitaria Sassari; Italia Fil: Doucet O’Hare, Tara. National Institutes of Health; Estados Unidos Fil: Cheng, Y. H. Hank. National Institutes of Health; Estados Unidos Fil: Abrams, Rachel P. M.. National Institutes of Health; Estados Unidos Fil: Pasternack, Nicholas. National Institutes of Health; Estados Unidos Fil: Malik, Nasir. National Institutes of Health; Estados Unidos Fil: Bachani, Muzna. National Institutes of Health; Estados Unidos Fil: Disanza, Brianna. National Institutes of Health; Estados Unidos Fil: Maric, Dragan. National Institutes of Health; Estados Unidos Fil: Lee, Myoung Hwa. National Institutes of Health; Estados Unidos Fil: Wang, Herui. National Institutes of Health; Estados Unidos Fil: Santamaria, Ulisses. National Institutes of Health; Estados Unidos Fil: Li, Wenxue. National Institutes of Health; Estados Unidos Fil: Sampson, Kevon. National Institutes of Health; Estados Unidos Fil: Lorenzo Lopez, Juan Ramiro. National Institutes of Health; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; Argentina Fil: Sánchez Miguel, Ignacio Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; Argentina Fil: Mezghrani, Alexandre. National Institutes of Health; Estados Unidos. Centre National de la Recherche Scientifique; Francia Fil: Li, Yan. National Institutes of Health; Estados Unidos Fil: Sechi, Leonardo Antonio. National Institutes of Health; Estados Unidos Fil: Pineda, Sebastian. National Institutes of Health; Estados Unidos Fil: Heiman, Myriam. National Institutes of Health; Estados Unidos Fil: Kellis, Manolis. National Institutes of Health; Estados Unidos Fil: Steiner, Joseph. National Institutes of Health; Estados Unidos Fil: Nath, Avindra. National Institutes of Health; Estados Unidos |
| description |
TAR DNA-binding protein 43 (TDP-43) proteinopathy in brain cells is the hallmark of amyotrophic lateral sclerosis (ALS) but its cause remains elusive. Asparaginase-like-1 protein (ASRGL1) cleaves isoaspartates, which alter protein folding and susceptibility to proteolysis. ASRGL1 gene harbors a copy of the human endogenous retrovirus HML-2, whose overexpression contributes to ALS pathogenesis. Here we show that ASRGL1 expression was diminished in ALS brain samples by RNA sequencing, immunohistochemistry, and western blotting. TDP-43 and ASRGL1 colocalized in neurons but, in the absence of ASRGL1, TDP-43 aggregated in the cytoplasm. TDP-43 was found to be prone to isoaspartate formation and a substrate for ASRGL1. ASRGL1 silencing triggered accumulation of misfolded, fragmented, phosphorylated and mislocalized TDP-43 in cultured neurons and motor cortex of female mice. Overexpression of ASRGL1 restored neuronal viability. Overexpression of HML-2 led to ASRGL1 silencing. Loss of ASRGL1 leading to TDP-43 aggregation may be a critical mechanism in ALS pathophysiology. |
| publishDate |
2024 |
| dc.date.none.fl_str_mv |
2024-05 |
| 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 |
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article |
| status_str |
publishedVersion |
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http://hdl.handle.net/11336/266094 Garcia Montojo, Marta; Fathi, Saeed; Rastegar, Cyrus; Simula, Elena Rita; Doucet O’Hare, Tara; et al.; TDP-43 proteinopathy in ALS is triggered by loss of ASRGL1 and associated with HML-2 expression; Nature; Nature Communications; 15; 1; 5-2024; 1-24 2041-1723 CONICET Digital CONICET |
| url |
http://hdl.handle.net/11336/266094 |
| identifier_str_mv |
Garcia Montojo, Marta; Fathi, Saeed; Rastegar, Cyrus; Simula, Elena Rita; Doucet O’Hare, Tara; et al.; TDP-43 proteinopathy in ALS is triggered by loss of ASRGL1 and associated with HML-2 expression; Nature; Nature Communications; 15; 1; 5-2024; 1-24 2041-1723 CONICET Digital CONICET |
| dc.language.none.fl_str_mv |
eng |
| language |
eng |
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info:eu-repo/semantics/altIdentifier/doi/10.1038/s41467-024-48488-7 info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s41467-024-48488-7 |
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openAccess |
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application/pdf application/pdf |
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Nature |
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Nature |
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dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar |
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