Autophagy in Spinocerebellar ataxia type 2, a dysregulated pathway, and a target for therapy

Abstract Spinocerebellar ataxia type 2 (SCA2) is an incurable and genetic neurodegenerative disorder. The disease is characterized by progressive degeneration of several brain regions, resulting in severe motor and non-motor clinical manifestations. The mutation causing SCA2 disease is an abnormal e...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Adriana Marcelo, Inês T. Afonso, Ricardo Afonso-Reis, David V. C. Brito, Rafael G. Costa, Ana Rosa, João Alves-Cruzeiro, Benedita Ferreira, Carina Henriques, Rui J. Nobre, Carlos A. Matos, Luís Pereira de Almeida, Clévio Nóbrega
Formato:	article
Lenguaje:	EN
Publicado:	Nature Publishing Group 2021
Materias:	Cytology QH573-671
Acceso en línea:	https://doaj.org/article/b63aca6d2a754206b576ac751ce40616
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:b63aca6d2a754206b576ac751ce40616
record_format	dspace
spelling	oai:doaj.org-article:b63aca6d2a754206b576ac751ce406162021-12-05T12:04:23ZAutophagy in Spinocerebellar ataxia type 2, a dysregulated pathway, and a target for therapy10.1038/s41419-021-04404-12041-4889https://doaj.org/article/b63aca6d2a754206b576ac751ce406162021-11-01T00:00:00Zhttps://doi.org/10.1038/s41419-021-04404-1https://doaj.org/toc/2041-4889Abstract Spinocerebellar ataxia type 2 (SCA2) is an incurable and genetic neurodegenerative disorder. The disease is characterized by progressive degeneration of several brain regions, resulting in severe motor and non-motor clinical manifestations. The mutation causing SCA2 disease is an abnormal expansion of CAG trinucleotide repeats in the ATXN2 gene, leading to a toxic expanded polyglutamine segment in the translated ataxin-2 protein. While the genetic cause is well established, the exact mechanisms behind neuronal death induced by mutant ataxin-2 are not yet completely understood. Thus, the goal of this study is to investigate the role of autophagy in SCA2 pathogenesis and investigate its suitability as a target for therapeutic intervention. For that, we developed and characterized a new striatal lentiviral mouse model that resembled several neuropathological hallmarks observed in SCA2 disease, including formation of aggregates, neuronal marker loss, cell death and neuroinflammation. In this new model, we analyzed autophagic markers, which were also analyzed in a SCA2 cellular model and in human post-mortem brain samples. Our results showed altered levels of SQSTM1 and LC3B in cells and tissues expressing mutant ataxin-2. Moreover, an abnormal accumulation of these markers was detected in SCA2 patients’ striatum and cerebellum. Importantly, the molecular activation of autophagy, using the compound cordycepin, mitigated the phenotypic alterations observed in disease models. Overall, our study suggests an important role for autophagy in the context of SCA2 pathology, proposing that targeting this pathway could be a potential target to treat SCA2 patients.Adriana MarceloInês T. AfonsoRicardo Afonso-ReisDavid V. C. BritoRafael G. CostaAna RosaJoão Alves-CruzeiroBenedita FerreiraCarina HenriquesRui J. NobreCarlos A. MatosLuís Pereira de AlmeidaClévio NóbregaNature Publishing GrouparticleCytologyQH573-671ENCell Death and Disease, Vol 12, Iss 12, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Cytology QH573-671
spellingShingle	Cytology QH573-671 Adriana Marcelo Inês T. Afonso Ricardo Afonso-Reis David V. C. Brito Rafael G. Costa Ana Rosa João Alves-Cruzeiro Benedita Ferreira Carina Henriques Rui J. Nobre Carlos A. Matos Luís Pereira de Almeida Clévio Nóbrega Autophagy in Spinocerebellar ataxia type 2, a dysregulated pathway, and a target for therapy
description	Abstract Spinocerebellar ataxia type 2 (SCA2) is an incurable and genetic neurodegenerative disorder. The disease is characterized by progressive degeneration of several brain regions, resulting in severe motor and non-motor clinical manifestations. The mutation causing SCA2 disease is an abnormal expansion of CAG trinucleotide repeats in the ATXN2 gene, leading to a toxic expanded polyglutamine segment in the translated ataxin-2 protein. While the genetic cause is well established, the exact mechanisms behind neuronal death induced by mutant ataxin-2 are not yet completely understood. Thus, the goal of this study is to investigate the role of autophagy in SCA2 pathogenesis and investigate its suitability as a target for therapeutic intervention. For that, we developed and characterized a new striatal lentiviral mouse model that resembled several neuropathological hallmarks observed in SCA2 disease, including formation of aggregates, neuronal marker loss, cell death and neuroinflammation. In this new model, we analyzed autophagic markers, which were also analyzed in a SCA2 cellular model and in human post-mortem brain samples. Our results showed altered levels of SQSTM1 and LC3B in cells and tissues expressing mutant ataxin-2. Moreover, an abnormal accumulation of these markers was detected in SCA2 patients’ striatum and cerebellum. Importantly, the molecular activation of autophagy, using the compound cordycepin, mitigated the phenotypic alterations observed in disease models. Overall, our study suggests an important role for autophagy in the context of SCA2 pathology, proposing that targeting this pathway could be a potential target to treat SCA2 patients.
format	article
author	Adriana Marcelo Inês T. Afonso Ricardo Afonso-Reis David V. C. Brito Rafael G. Costa Ana Rosa João Alves-Cruzeiro Benedita Ferreira Carina Henriques Rui J. Nobre Carlos A. Matos Luís Pereira de Almeida Clévio Nóbrega
author_facet	Adriana Marcelo Inês T. Afonso Ricardo Afonso-Reis David V. C. Brito Rafael G. Costa Ana Rosa João Alves-Cruzeiro Benedita Ferreira Carina Henriques Rui J. Nobre Carlos A. Matos Luís Pereira de Almeida Clévio Nóbrega
author_sort	Adriana Marcelo
title	Autophagy in Spinocerebellar ataxia type 2, a dysregulated pathway, and a target for therapy
title_short	Autophagy in Spinocerebellar ataxia type 2, a dysregulated pathway, and a target for therapy
title_full	Autophagy in Spinocerebellar ataxia type 2, a dysregulated pathway, and a target for therapy
title_fullStr	Autophagy in Spinocerebellar ataxia type 2, a dysregulated pathway, and a target for therapy
title_full_unstemmed	Autophagy in Spinocerebellar ataxia type 2, a dysregulated pathway, and a target for therapy
title_sort	autophagy in spinocerebellar ataxia type 2, a dysregulated pathway, and a target for therapy
publisher	Nature Publishing Group
publishDate	2021
url	https://doaj.org/article/b63aca6d2a754206b576ac751ce40616
work_keys_str_mv	AT adrianamarcelo autophagyinspinocerebellarataxiatype2adysregulatedpathwayandatargetfortherapy AT inestafonso autophagyinspinocerebellarataxiatype2adysregulatedpathwayandatargetfortherapy AT ricardoafonsoreis autophagyinspinocerebellarataxiatype2adysregulatedpathwayandatargetfortherapy AT davidvcbrito autophagyinspinocerebellarataxiatype2adysregulatedpathwayandatargetfortherapy AT rafaelgcosta autophagyinspinocerebellarataxiatype2adysregulatedpathwayandatargetfortherapy AT anarosa autophagyinspinocerebellarataxiatype2adysregulatedpathwayandatargetfortherapy AT joaoalvescruzeiro autophagyinspinocerebellarataxiatype2adysregulatedpathwayandatargetfortherapy AT beneditaferreira autophagyinspinocerebellarataxiatype2adysregulatedpathwayandatargetfortherapy AT carinahenriques autophagyinspinocerebellarataxiatype2adysregulatedpathwayandatargetfortherapy AT ruijnobre autophagyinspinocerebellarataxiatype2adysregulatedpathwayandatargetfortherapy AT carlosamatos autophagyinspinocerebellarataxiatype2adysregulatedpathwayandatargetfortherapy AT luispereiradealmeida autophagyinspinocerebellarataxiatype2adysregulatedpathwayandatargetfortherapy AT clevionobrega autophagyinspinocerebellarataxiatype2adysregulatedpathwayandatargetfortherapy
_version_	1718372278998138880

Autophagy in Spinocerebellar ataxia type 2, a dysregulated pathway, and a target for therapy

Ejemplares similares