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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...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2023
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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 |
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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 |
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