α-Synuclein interacts directly but reversibly with psychosine: implications for α-synucleinopathies

Autores
Abdelkarim, Hazem; Marshall, Michael S.; Scesa, Giuseppe; Smith, Rachael A.; Rue, Emily; Marshall, Jeffrey; Elackattu, Vince; Stoskute, Monika; Issa, Yazan; Santos, Marta; Nguyen, Duc; Hauck, Zane; Van Breemen, Richard B.; Celej, Maria Soledad; Gaponenko, Vadim; Bongarzone, Ernesto R.
Año de publicación
2018
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Aggregation of α-synuclein, the hallmark of α-synucleinopathies such as Parkinson´s disease, occurs in various glycosphingolipidoses. Although α-synuclein aggregation correlates with deficiencies in the lysosomal degradation of glycosphingolipids (GSL), the mechanism(s) involved in this aggregation remains unclear. We previously described the aggregation of α-synuclein in Krabbe´s disease (KD), a neurodegenerative glycosphingolipidosis caused by lysosomal deficiency of galactosyl-ceramidase (GALC) and the accumulation of the GSL psychosine. Here, we used a multi-pronged approach including genetic, biophysical and biochemical techniques to determine the pathogenic contribution, reversibility, and molecular mechanism of aggregation of α-synuclein in KD. While genetic knock-out of α-synuclein reduces, but does not completely prevent, neurological signs in a mouse model of KD, genetic correction of GALC deficiency completely prevents α-synuclein aggregation. We show that psychosine forms hydrophilic clusters and binds the C-terminus of α-synuclein through its amino group and sugar moiety, suggesting that psychosine promotes an open/aggregation-prone conformation of α-synuclein. Dopamine and carbidopa reverse the structural changes of psychosine by mediating a closed/aggregation-resistant conformation of α-synuclein. Our results underscore the therapeutic potential of lysosomal correction and small molecules to reduce neuronal burden in α-synucleinopathies, and provide a mechanistic understanding of α-synuclein aggregation in glycosphingolipidoses.
Fil: Abdelkarim, Hazem. University of Illinois; Estados Unidos
Fil: Marshall, Michael S.. University of Illinois; Estados Unidos
Fil: Scesa, Giuseppe. University of Illinois; Estados Unidos
Fil: Smith, Rachael A.. University of Illinois; Estados Unidos
Fil: Rue, Emily. University of Illinois; Estados Unidos
Fil: Marshall, Jeffrey. University of Illinois; Estados Unidos
Fil: Elackattu, Vince. University Of Illinois Chicago; Estados Unidos
Fil: Stoskute, Monika. University Of Illinois Chicago; Estados Unidos
Fil: Issa, Yazan. University Of Illinois Chicago; Estados Unidos
Fil: Santos, Marta. University Of Illinois Chicago; Estados Unidos
Fil: Nguyen, Duc. University Of Illinois Chicago; Estados Unidos
Fil: Hauck, Zane. University Of Illinois Chicago; Estados Unidos
Fil: Van Breemen, Richard B.. University Of Illinois Chicago; Estados Unidos
Fil: Celej, Maria Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina
Fil: Gaponenko, Vadim. University Of Illinois Chicago; Estados Unidos
Fil: Bongarzone, Ernesto R.. University Of Illinois Chicago; Estados Unidos
Materia
SYNUCLEIN
PSYCHOSINE
KRABBE
SYNUCLEINOPATHIES
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/106534
Acceder
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network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling α-Synuclein interacts directly but reversibly with psychosine: implications for α-synucleinopathiesAbdelkarim, HazemMarshall, Michael S.Scesa, GiuseppeSmith, Rachael A.Rue, EmilyMarshall, JeffreyElackattu, VinceStoskute, MonikaIssa, YazanSantos, MartaNguyen, DucHauck, ZaneVan Breemen, Richard B.Celej, Maria SoledadGaponenko, VadimBongarzone, Ernesto R.SYNUCLEINPSYCHOSINEKRABBESYNUCLEINOPATHIEShttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Aggregation of α-synuclein, the hallmark of α-synucleinopathies such as Parkinson´s disease, occurs in various glycosphingolipidoses. Although α-synuclein aggregation correlates with deficiencies in the lysosomal degradation of glycosphingolipids (GSL), the mechanism(s) involved in this aggregation remains unclear. We previously described the aggregation of α-synuclein in Krabbe´s disease (KD), a neurodegenerative glycosphingolipidosis caused by lysosomal deficiency of galactosyl-ceramidase (GALC) and the accumulation of the GSL psychosine. Here, we used a multi-pronged approach including genetic, biophysical and biochemical techniques to determine the pathogenic contribution, reversibility, and molecular mechanism of aggregation of α-synuclein in KD. While genetic knock-out of α-synuclein reduces, but does not completely prevent, neurological signs in a mouse model of KD, genetic correction of GALC deficiency completely prevents α-synuclein aggregation. We show that psychosine forms hydrophilic clusters and binds the C-terminus of α-synuclein through its amino group and sugar moiety, suggesting that psychosine promotes an open/aggregation-prone conformation of α-synuclein. Dopamine and carbidopa reverse the structural changes of psychosine by mediating a closed/aggregation-resistant conformation of α-synuclein. Our results underscore the therapeutic potential of lysosomal correction and small molecules to reduce neuronal burden in α-synucleinopathies, and provide a mechanistic understanding of α-synuclein aggregation in glycosphingolipidoses.Fil: Abdelkarim, Hazem. University of Illinois; Estados UnidosFil: Marshall, Michael S.. University of Illinois; Estados UnidosFil: Scesa, Giuseppe. University of Illinois; Estados UnidosFil: Smith, Rachael A.. University of Illinois; Estados UnidosFil: Rue, Emily. University of Illinois; Estados UnidosFil: Marshall, Jeffrey. University of Illinois; Estados UnidosFil: Elackattu, Vince. University Of Illinois Chicago; Estados UnidosFil: Stoskute, Monika. University Of Illinois Chicago; Estados UnidosFil: Issa, Yazan. University Of Illinois Chicago; Estados UnidosFil: Santos, Marta. University Of Illinois Chicago; Estados UnidosFil: Nguyen, Duc. University Of Illinois Chicago; Estados UnidosFil: Hauck, Zane. University Of Illinois Chicago; Estados UnidosFil: Van Breemen, Richard B.. University Of Illinois Chicago; Estados UnidosFil: Celej, Maria Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Gaponenko, Vadim. University Of Illinois Chicago; Estados UnidosFil: Bongarzone, Ernesto R.. University Of Illinois Chicago; Estados UnidosNature Publishing Group2018-08info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/106534Abdelkarim, Hazem; Marshall, Michael S.; Scesa, Giuseppe; Smith, Rachael A.; Rue, Emily; et al.; α-Synuclein interacts directly but reversibly with psychosine: implications for α-synucleinopathies; Nature Publishing Group; Scientific Reports; 8; 1; 8-20182045-2322CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://www.nature.com/articles/s41598-018-30808-9info:eu-repo/semantics/altIdentifier/doi/10.1038/s41598-018-30808-9info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6102231/info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-10T13:07:52Zoai:ri.conicet.gov.ar:11336/106534instacron: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 13:07:52.263CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv α-Synuclein interacts directly but reversibly with psychosine: implications for α-synucleinopathies
title α-Synuclein interacts directly but reversibly with psychosine: implications for α-synucleinopathies
spellingShingle α-Synuclein interacts directly but reversibly with psychosine: implications for α-synucleinopathies
Abdelkarim, Hazem
SYNUCLEIN
PSYCHOSINE
KRABBE
SYNUCLEINOPATHIES
title_short α-Synuclein interacts directly but reversibly with psychosine: implications for α-synucleinopathies
title_full α-Synuclein interacts directly but reversibly with psychosine: implications for α-synucleinopathies
title_fullStr α-Synuclein interacts directly but reversibly with psychosine: implications for α-synucleinopathies
title_full_unstemmed α-Synuclein interacts directly but reversibly with psychosine: implications for α-synucleinopathies
title_sort α-Synuclein interacts directly but reversibly with psychosine: implications for α-synucleinopathies
dc.creator.none.fl_str_mv Abdelkarim, Hazem
Marshall, Michael S.
Scesa, Giuseppe
Smith, Rachael A.
Rue, Emily
Marshall, Jeffrey
Elackattu, Vince
Stoskute, Monika
Issa, Yazan
Santos, Marta
Nguyen, Duc
Hauck, Zane
Van Breemen, Richard B.
Celej, Maria Soledad
Gaponenko, Vadim
Bongarzone, Ernesto R.
author Abdelkarim, Hazem
author_facet Abdelkarim, Hazem
Marshall, Michael S.
Scesa, Giuseppe
Smith, Rachael A.
Rue, Emily
Marshall, Jeffrey
Elackattu, Vince
Stoskute, Monika
Issa, Yazan
Santos, Marta
Nguyen, Duc
Hauck, Zane
Van Breemen, Richard B.
Celej, Maria Soledad
Gaponenko, Vadim
Bongarzone, Ernesto R.
author_role author
author2 Marshall, Michael S.
Scesa, Giuseppe
Smith, Rachael A.
Rue, Emily
Marshall, Jeffrey
Elackattu, Vince
Stoskute, Monika
Issa, Yazan
Santos, Marta
Nguyen, Duc
Hauck, Zane
Van Breemen, Richard B.
Celej, Maria Soledad
Gaponenko, Vadim
Bongarzone, Ernesto R.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv SYNUCLEIN
PSYCHOSINE
KRABBE
SYNUCLEINOPATHIES
topic SYNUCLEIN
PSYCHOSINE
KRABBE
SYNUCLEINOPATHIES
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Aggregation of α-synuclein, the hallmark of α-synucleinopathies such as Parkinson´s disease, occurs in various glycosphingolipidoses. Although α-synuclein aggregation correlates with deficiencies in the lysosomal degradation of glycosphingolipids (GSL), the mechanism(s) involved in this aggregation remains unclear. We previously described the aggregation of α-synuclein in Krabbe´s disease (KD), a neurodegenerative glycosphingolipidosis caused by lysosomal deficiency of galactosyl-ceramidase (GALC) and the accumulation of the GSL psychosine. Here, we used a multi-pronged approach including genetic, biophysical and biochemical techniques to determine the pathogenic contribution, reversibility, and molecular mechanism of aggregation of α-synuclein in KD. While genetic knock-out of α-synuclein reduces, but does not completely prevent, neurological signs in a mouse model of KD, genetic correction of GALC deficiency completely prevents α-synuclein aggregation. We show that psychosine forms hydrophilic clusters and binds the C-terminus of α-synuclein through its amino group and sugar moiety, suggesting that psychosine promotes an open/aggregation-prone conformation of α-synuclein. Dopamine and carbidopa reverse the structural changes of psychosine by mediating a closed/aggregation-resistant conformation of α-synuclein. Our results underscore the therapeutic potential of lysosomal correction and small molecules to reduce neuronal burden in α-synucleinopathies, and provide a mechanistic understanding of α-synuclein aggregation in glycosphingolipidoses.
Fil: Abdelkarim, Hazem. University of Illinois; Estados Unidos
Fil: Marshall, Michael S.. University of Illinois; Estados Unidos
Fil: Scesa, Giuseppe. University of Illinois; Estados Unidos
Fil: Smith, Rachael A.. University of Illinois; Estados Unidos
Fil: Rue, Emily. University of Illinois; Estados Unidos
Fil: Marshall, Jeffrey. University of Illinois; Estados Unidos
Fil: Elackattu, Vince. University Of Illinois Chicago; Estados Unidos
Fil: Stoskute, Monika. University Of Illinois Chicago; Estados Unidos
Fil: Issa, Yazan. University Of Illinois Chicago; Estados Unidos
Fil: Santos, Marta. University Of Illinois Chicago; Estados Unidos
Fil: Nguyen, Duc. University Of Illinois Chicago; Estados Unidos
Fil: Hauck, Zane. University Of Illinois Chicago; Estados Unidos
Fil: Van Breemen, Richard B.. University Of Illinois Chicago; Estados Unidos
Fil: Celej, Maria Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina
Fil: Gaponenko, Vadim. University Of Illinois Chicago; Estados Unidos
Fil: Bongarzone, Ernesto R.. University Of Illinois Chicago; Estados Unidos
description Aggregation of α-synuclein, the hallmark of α-synucleinopathies such as Parkinson´s disease, occurs in various glycosphingolipidoses. Although α-synuclein aggregation correlates with deficiencies in the lysosomal degradation of glycosphingolipids (GSL), the mechanism(s) involved in this aggregation remains unclear. We previously described the aggregation of α-synuclein in Krabbe´s disease (KD), a neurodegenerative glycosphingolipidosis caused by lysosomal deficiency of galactosyl-ceramidase (GALC) and the accumulation of the GSL psychosine. Here, we used a multi-pronged approach including genetic, biophysical and biochemical techniques to determine the pathogenic contribution, reversibility, and molecular mechanism of aggregation of α-synuclein in KD. While genetic knock-out of α-synuclein reduces, but does not completely prevent, neurological signs in a mouse model of KD, genetic correction of GALC deficiency completely prevents α-synuclein aggregation. We show that psychosine forms hydrophilic clusters and binds the C-terminus of α-synuclein through its amino group and sugar moiety, suggesting that psychosine promotes an open/aggregation-prone conformation of α-synuclein. Dopamine and carbidopa reverse the structural changes of psychosine by mediating a closed/aggregation-resistant conformation of α-synuclein. Our results underscore the therapeutic potential of lysosomal correction and small molecules to reduce neuronal burden in α-synucleinopathies, and provide a mechanistic understanding of α-synuclein aggregation in glycosphingolipidoses.
publishDate 2018
dc.date.none.fl_str_mv 2018-08
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/11336/106534
Abdelkarim, Hazem; Marshall, Michael S.; Scesa, Giuseppe; Smith, Rachael A.; Rue, Emily; et al.; α-Synuclein interacts directly but reversibly with psychosine: implications for α-synucleinopathies; Nature Publishing Group; Scientific Reports; 8; 1; 8-2018
2045-2322
CONICET Digital
CONICET
url http://hdl.handle.net/11336/106534
identifier_str_mv Abdelkarim, Hazem; Marshall, Michael S.; Scesa, Giuseppe; Smith, Rachael A.; Rue, Emily; et al.; α-Synuclein interacts directly but reversibly with psychosine: implications for α-synucleinopathies; Nature Publishing Group; Scientific Reports; 8; 1; 8-2018
2045-2322
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://www.nature.com/articles/s41598-018-30808-9
info:eu-repo/semantics/altIdentifier/doi/10.1038/s41598-018-30808-9
info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6102231/
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
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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score 12.993085

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