Cargando…

Unconventional Source of Neurotoxic Protein Aggregation from Organelle Off-Target Bax∆2 in Alzheimer’s Disease

Protein aggregates are a hallmark of Alzheimer’s disease (AD). Extensive studies have focused on β-amyloid plaques and Tau tangles. Here, we illustrate a novel source of protein aggregates in AD neurons from organelle off-target proteins. Bax is a mitochondrial pore-forming pro-death protein. What h...

Descripción completa

Detalles Bibliográficos
Autores principales: Yao, Qi, Mascarenhas dos Santos, Anne Caroline, Zhang, Huaiyuan, Mañas, Adriana, Hussaini, Ammarah, Kim, Ujin, Xu, Congtai, Basheer, Sana, Tasaki, Shinya, Xiang, Jialing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10296721/
https://www.ncbi.nlm.nih.gov/pubmed/37371550
http://dx.doi.org/10.3390/biom13060970
_version_ 1785063716675387392
author Yao, Qi
Mascarenhas dos Santos, Anne Caroline
Zhang, Huaiyuan
Mañas, Adriana
Hussaini, Ammarah
Kim, Ujin
Xu, Congtai
Basheer, Sana
Tasaki, Shinya
Xiang, Jialing
author_facet Yao, Qi
Mascarenhas dos Santos, Anne Caroline
Zhang, Huaiyuan
Mañas, Adriana
Hussaini, Ammarah
Kim, Ujin
Xu, Congtai
Basheer, Sana
Tasaki, Shinya
Xiang, Jialing
author_sort Yao, Qi
collection PubMed
description Protein aggregates are a hallmark of Alzheimer’s disease (AD). Extensive studies have focused on β-amyloid plaques and Tau tangles. Here, we illustrate a novel source of protein aggregates in AD neurons from organelle off-target proteins. Bax is a mitochondrial pore-forming pro-death protein. What happens to Bax if it fails to target mitochondria? We previously showed that a mitochondrial target-deficient alternatively spliced variant, Bax∆2, formed large cytosolic protein aggregates and triggered caspase 8-mediated cell death. Bax∆2 protein levels were low in most normal organs and the proteins were quickly degraded in cancer. Here, we found that 85% of AD patients had Bax∆2 required alternative splicing. Increased Bax∆2 proteins were mostly accumulated in neurons of AD-susceptible brain regions. Intracellularly, Bax∆2 aggregates distributed independently of Tau tangles. Interestingly, Bax∆2 aggregates triggered the formation of stress granules (SGs), a large protein-RNA complex involved in AD pathogenesis. Although the functional domains required for aggregation and cell death are the same as in cancer cells, Bax∆2 relied on SGs, not caspase 8, for neuronal cell death. These results imply that the aggregation of organelle off-target proteins, such as Bax∆2, broadens the scope of traditional AD pathogenic proteins that contribute to the neuronal stress responses and AD pathogenesis.
format Online
Article
Text
id pubmed-10296721
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-102967212023-06-28 Unconventional Source of Neurotoxic Protein Aggregation from Organelle Off-Target Bax∆2 in Alzheimer’s Disease Yao, Qi Mascarenhas dos Santos, Anne Caroline Zhang, Huaiyuan Mañas, Adriana Hussaini, Ammarah Kim, Ujin Xu, Congtai Basheer, Sana Tasaki, Shinya Xiang, Jialing Biomolecules Article Protein aggregates are a hallmark of Alzheimer’s disease (AD). Extensive studies have focused on β-amyloid plaques and Tau tangles. Here, we illustrate a novel source of protein aggregates in AD neurons from organelle off-target proteins. Bax is a mitochondrial pore-forming pro-death protein. What happens to Bax if it fails to target mitochondria? We previously showed that a mitochondrial target-deficient alternatively spliced variant, Bax∆2, formed large cytosolic protein aggregates and triggered caspase 8-mediated cell death. Bax∆2 protein levels were low in most normal organs and the proteins were quickly degraded in cancer. Here, we found that 85% of AD patients had Bax∆2 required alternative splicing. Increased Bax∆2 proteins were mostly accumulated in neurons of AD-susceptible brain regions. Intracellularly, Bax∆2 aggregates distributed independently of Tau tangles. Interestingly, Bax∆2 aggregates triggered the formation of stress granules (SGs), a large protein-RNA complex involved in AD pathogenesis. Although the functional domains required for aggregation and cell death are the same as in cancer cells, Bax∆2 relied on SGs, not caspase 8, for neuronal cell death. These results imply that the aggregation of organelle off-target proteins, such as Bax∆2, broadens the scope of traditional AD pathogenic proteins that contribute to the neuronal stress responses and AD pathogenesis. MDPI 2023-06-10 /pmc/articles/PMC10296721/ /pubmed/37371550 http://dx.doi.org/10.3390/biom13060970 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Yao, Qi
Mascarenhas dos Santos, Anne Caroline
Zhang, Huaiyuan
Mañas, Adriana
Hussaini, Ammarah
Kim, Ujin
Xu, Congtai
Basheer, Sana
Tasaki, Shinya
Xiang, Jialing
Unconventional Source of Neurotoxic Protein Aggregation from Organelle Off-Target Bax∆2 in Alzheimer’s Disease
title Unconventional Source of Neurotoxic Protein Aggregation from Organelle Off-Target Bax∆2 in Alzheimer’s Disease
title_full Unconventional Source of Neurotoxic Protein Aggregation from Organelle Off-Target Bax∆2 in Alzheimer’s Disease
title_fullStr Unconventional Source of Neurotoxic Protein Aggregation from Organelle Off-Target Bax∆2 in Alzheimer’s Disease
title_full_unstemmed Unconventional Source of Neurotoxic Protein Aggregation from Organelle Off-Target Bax∆2 in Alzheimer’s Disease
title_short Unconventional Source of Neurotoxic Protein Aggregation from Organelle Off-Target Bax∆2 in Alzheimer’s Disease
title_sort unconventional source of neurotoxic protein aggregation from organelle off-target bax∆2 in alzheimer’s disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10296721/
https://www.ncbi.nlm.nih.gov/pubmed/37371550
http://dx.doi.org/10.3390/biom13060970
work_keys_str_mv AT yaoqi unconventionalsourceofneurotoxicproteinaggregationfromorganelleofftargetbax2inalzheimersdisease
AT mascarenhasdossantosannecaroline unconventionalsourceofneurotoxicproteinaggregationfromorganelleofftargetbax2inalzheimersdisease
AT zhanghuaiyuan unconventionalsourceofneurotoxicproteinaggregationfromorganelleofftargetbax2inalzheimersdisease
AT manasadriana unconventionalsourceofneurotoxicproteinaggregationfromorganelleofftargetbax2inalzheimersdisease
AT hussainiammarah unconventionalsourceofneurotoxicproteinaggregationfromorganelleofftargetbax2inalzheimersdisease
AT kimujin unconventionalsourceofneurotoxicproteinaggregationfromorganelleofftargetbax2inalzheimersdisease
AT xucongtai unconventionalsourceofneurotoxicproteinaggregationfromorganelleofftargetbax2inalzheimersdisease
AT basheersana unconventionalsourceofneurotoxicproteinaggregationfromorganelleofftargetbax2inalzheimersdisease
AT tasakishinya unconventionalsourceofneurotoxicproteinaggregationfromorganelleofftargetbax2inalzheimersdisease
AT xiangjialing unconventionalsourceofneurotoxicproteinaggregationfromorganelleofftargetbax2inalzheimersdisease