Unconventional Source of Neurotoxic Protein Aggregation from Organelle Off-Target Bax∆2 in Alzheimer's Disease
(2023) In Biomolecules 13(6).- Abstract
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... (More)
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.
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- author
- Yao, Qi ; Mascarenhas Dos Santos, Anne Caroline ; Zhang, Huaiyuan ; Mañas, Adriana LU ; Hussaini, Ammarah ; Kim, Ujin ; Xu, Congtai ; Basheer, Sana ; Tasaki, Shinya and Xiang, Jialing
- organization
- publishing date
- 2023-06-10
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Humans, Alzheimer Disease/metabolism, Protein Aggregates, bcl-2-Associated X Protein/genetics, Amyloid beta-Peptides/metabolism, Mitochondria/metabolism, Neurotoxicity Syndromes, tau Proteins/genetics
- in
- Biomolecules
- volume
- 13
- issue
- 6
- article number
- 970
- publisher
- MDPI AG
- external identifiers
-
- scopus:85163867160
- pmid:37371550
- ISSN
- 2218-273X
- DOI
- 10.3390/biom13060970
- language
- English
- LU publication?
- yes
- id
- 4b2447f2-80e8-4893-9521-c271c8fb6da0
- date added to LUP
- 2023-08-01 08:48:34
- date last changed
- 2024-04-20 00:04:57
@article{4b2447f2-80e8-4893-9521-c271c8fb6da0,
abstract = {{<p>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.</p>}},
author = {{Yao, Qi and Mascarenhas Dos Santos, Anne Caroline and Zhang, Huaiyuan and Mañas, Adriana and Hussaini, Ammarah and Kim, Ujin and Xu, Congtai and Basheer, Sana and Tasaki, Shinya and Xiang, Jialing}},
issn = {{2218-273X}},
keywords = {{Humans; Alzheimer Disease/metabolism; Protein Aggregates; bcl-2-Associated X Protein/genetics; Amyloid beta-Peptides/metabolism; Mitochondria/metabolism; Neurotoxicity Syndromes; tau Proteins/genetics}},
language = {{eng}},
month = {{06}},
number = {{6}},
publisher = {{MDPI AG}},
series = {{Biomolecules}},
title = {{Unconventional Source of Neurotoxic Protein Aggregation from Organelle Off-Target Bax∆2 in Alzheimer's Disease}},
url = {{http://dx.doi.org/10.3390/biom13060970}},
doi = {{10.3390/biom13060970}},
volume = {{13}},
year = {{2023}},
}