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Unconventional Sour...
Unconventional Source of Neurotoxic Protein Aggregation from Organelle Off-Target Bax∆2 in Alzheimer's Disease
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- Yao, Qi (författare)
- Illinois Institute of Technology
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- Mascarenhas Dos Santos, Anne Caroline (författare)
- Illinois Institute of Technology
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- Zhang, Huaiyuan (författare)
- Illinois Institute of Technology
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- Mañas, Adriana (författare)
- Lund University,Lunds universitet,Molekylär barnonkologi,Forskargrupper vid Lunds universitet,Molecular Pediatric Oncology,Lund University Research Groups
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- Hussaini, Ammarah (författare)
- Illinois Institute of Technology
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- Kim, Ujin (författare)
- Illinois Institute of Technology
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- Xu, Congtai (författare)
- Illinois Institute of Technology
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- Basheer, Sana (författare)
- Illinois Institute of Technology
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- Tasaki, Shinya (författare)
- Rush University Medical Center Chicago
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- Xiang, Jialing (författare)
- Illinois Institute of Technology
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(creator_code:org_t)
- 2023
- 2023
- Engelska.
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Ingår i: Biomolecules. - 2218-273X. ; 13:6
- Relaterad länk:
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http://dx.doi.org/10... (free)
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https://lup.lub.lu.s...
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https://doi.org/10.3...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Nyckelord
- Humans
- Alzheimer Disease/metabolism
- Protein Aggregates
- bcl-2-Associated X Protein/genetics
- Amyloid beta-Peptides/metabolism
- Mitochondria/metabolism
- Neurotoxicity Syndromes
- tau Proteins/genetics
Publikations- och innehållstyp
- art (ämneskategori)
- ref (ämneskategori)
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