BH3-only proteins Puma and Beclin1 regulate autophagic death in neurons in response to Amyloid-β

Abstract Alzheimer’s disease (AD) is characterized by accumulation of senile amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles causing progressive loss of synapse and neuronal death. Out of the various neuron death modalities, autophagy and apoptosis are reported to be the major death parad...

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Autores principales:	Akash Saha, Suraiya Saleem, Paidi Ramesh Kumar, Subhas C. Biswas
Formato:	article
Lenguaje:	EN
Publicado:	Nature Publishing Group 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Cytology QH573-671
Acceso en línea:	https://doaj.org/article/131fddba260544bba6cd6f9e074fe80b
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spelling	oai:doaj.org-article:131fddba260544bba6cd6f9e074fe80b2021-11-21T12:08:51ZBH3-only proteins Puma and Beclin1 regulate autophagic death in neurons in response to Amyloid-β10.1038/s41420-021-00748-x2058-7716https://doaj.org/article/131fddba260544bba6cd6f9e074fe80b2021-11-01T00:00:00Zhttps://doi.org/10.1038/s41420-021-00748-xhttps://doaj.org/toc/2058-7716Abstract Alzheimer’s disease (AD) is characterized by accumulation of senile amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles causing progressive loss of synapse and neuronal death. Out of the various neuron death modalities, autophagy and apoptosis are reported to be the major death paradigms in AD. However, how these two processes lead to neuronal loss is still inconspicuous. Here we report that under Aβ toxicity, aberrant autophagy is induced with inefficient autophagic flux in neurons. Simultaneous activation of both autophagy and apoptosis are seen in primary cortical neurons as well as in transgenic mice brains. We found that induction of autophagy by rapamycin is detrimental for neurons; whereas downregulation of Beclin1, an important autophagy inducing protein, provides significant protection in Aβ treated neuronal cells by blocking cytochrome-c release from the mitochondria. We further report that downregulation of Puma, a BH3-only pro-apoptotic protein, inhibits the induction of aberrant autophagy and also ameliorates the autophagy flux under the influence of Aβ. Notably, stereotactic administration of shRNAs against Puma and Beclin1 in adult Aβ-infused rat brains inhibits both apoptotic and autophagic pathways. The regulation of both of the death processes is brought about by the direct interaction between Puma and Beclin1 upon Aβ treatment. We conclude that both Beclin1 and Puma play essential roles in the neuronal death caused by the induction of aberrant autophagy in AD and targeting their interaction could be vital to understand the crosstalk of autophagy and apoptosis as well as to develop a potential therapeutic strategy in AD.Akash SahaSuraiya SaleemPaidi Ramesh KumarSubhas C. BiswasNature Publishing GrouparticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282CytologyQH573-671ENCell Death Discovery, Vol 7, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Cytology QH573-671
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Cytology QH573-671 Akash Saha Suraiya Saleem Paidi Ramesh Kumar Subhas C. Biswas BH3-only proteins Puma and Beclin1 regulate autophagic death in neurons in response to Amyloid-β
description	Abstract Alzheimer’s disease (AD) is characterized by accumulation of senile amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles causing progressive loss of synapse and neuronal death. Out of the various neuron death modalities, autophagy and apoptosis are reported to be the major death paradigms in AD. However, how these two processes lead to neuronal loss is still inconspicuous. Here we report that under Aβ toxicity, aberrant autophagy is induced with inefficient autophagic flux in neurons. Simultaneous activation of both autophagy and apoptosis are seen in primary cortical neurons as well as in transgenic mice brains. We found that induction of autophagy by rapamycin is detrimental for neurons; whereas downregulation of Beclin1, an important autophagy inducing protein, provides significant protection in Aβ treated neuronal cells by blocking cytochrome-c release from the mitochondria. We further report that downregulation of Puma, a BH3-only pro-apoptotic protein, inhibits the induction of aberrant autophagy and also ameliorates the autophagy flux under the influence of Aβ. Notably, stereotactic administration of shRNAs against Puma and Beclin1 in adult Aβ-infused rat brains inhibits both apoptotic and autophagic pathways. The regulation of both of the death processes is brought about by the direct interaction between Puma and Beclin1 upon Aβ treatment. We conclude that both Beclin1 and Puma play essential roles in the neuronal death caused by the induction of aberrant autophagy in AD and targeting their interaction could be vital to understand the crosstalk of autophagy and apoptosis as well as to develop a potential therapeutic strategy in AD.
format	article
author	Akash Saha Suraiya Saleem Paidi Ramesh Kumar Subhas C. Biswas
author_facet	Akash Saha Suraiya Saleem Paidi Ramesh Kumar Subhas C. Biswas
author_sort	Akash Saha
title	BH3-only proteins Puma and Beclin1 regulate autophagic death in neurons in response to Amyloid-β
title_short	BH3-only proteins Puma and Beclin1 regulate autophagic death in neurons in response to Amyloid-β
title_full	BH3-only proteins Puma and Beclin1 regulate autophagic death in neurons in response to Amyloid-β
title_fullStr	BH3-only proteins Puma and Beclin1 regulate autophagic death in neurons in response to Amyloid-β
title_full_unstemmed	BH3-only proteins Puma and Beclin1 regulate autophagic death in neurons in response to Amyloid-β
title_sort	bh3-only proteins puma and beclin1 regulate autophagic death in neurons in response to amyloid-β
publisher	Nature Publishing Group
publishDate	2021
url	https://doaj.org/article/131fddba260544bba6cd6f9e074fe80b
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BH3-only proteins Puma and Beclin1 regulate autophagic death in neurons in response to Amyloid-β

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