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Physiological Consequences of Targeting 14-3-3 and Its Interacting Partners in Neurodegenerative Diseases
The mammalian 14-3-3 family comprises seven intrinsically unstructured, evolutionarily conserved proteins that bind >200 protein targets, thereby modulating cell-signaling pathways. The presence of 14-3-3 proteins in cerebrospinal fluid provides a sensitive and specific biomarker of neuronal dama...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9779020/ https://www.ncbi.nlm.nih.gov/pubmed/36555098 http://dx.doi.org/10.3390/ijms232415457 |
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author | Ganne, Akshatha Balasubramaniam, Meenakshisundaram Mainali, Nirjal Atluri, Paavan Shmookler Reis, Robert J. Ayyadevara, Srinivas |
author_facet | Ganne, Akshatha Balasubramaniam, Meenakshisundaram Mainali, Nirjal Atluri, Paavan Shmookler Reis, Robert J. Ayyadevara, Srinivas |
author_sort | Ganne, Akshatha |
collection | PubMed |
description | The mammalian 14-3-3 family comprises seven intrinsically unstructured, evolutionarily conserved proteins that bind >200 protein targets, thereby modulating cell-signaling pathways. The presence of 14-3-3 proteins in cerebrospinal fluid provides a sensitive and specific biomarker of neuronal damage associated with Alzheimer’s disease (AD), Creutzfeldt–Jakob disease (CJD), spongiform encephalitis, brain cancers, and stroke. We observed significant enrichment of 14-3-3 paralogs G, S, and Z in human brain aggregates diagnostic of AD. We used intra-aggregate crosslinking to identify 14-3-3 interaction partners, all of which were significantly enriched in AD brain aggregates relative to controls. We screened FDA-approved drugs in silico for structures that could target the 14-3-3G/hexokinase interface, an interaction specific to aggregates and AD. C. elegans possesses only two 14-3-3 orthologs, which bind diverse proteins including DAF-16 (a FOXO transcription factor) and SIR-2.1 (a sensor of nutrients and stress), influencing lifespan. Top drug candidates were tested in C. elegans models of neurodegeneration-associated aggregation and in a human neuroblastoma cell-culture model of AD-like amyloidosis. Several drugs opposed aggregation in all models assessed and rescued behavioral deficits in C. elegans AD-like neuropathy models, suggesting that 14-3-3 proteins are instrumental in aggregate accrual and supporting the advancement of drugs targeting 14-3-3 protein complexes with their partners. |
format | Online Article Text |
id | pubmed-9779020 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-97790202022-12-23 Physiological Consequences of Targeting 14-3-3 and Its Interacting Partners in Neurodegenerative Diseases Ganne, Akshatha Balasubramaniam, Meenakshisundaram Mainali, Nirjal Atluri, Paavan Shmookler Reis, Robert J. Ayyadevara, Srinivas Int J Mol Sci Article The mammalian 14-3-3 family comprises seven intrinsically unstructured, evolutionarily conserved proteins that bind >200 protein targets, thereby modulating cell-signaling pathways. The presence of 14-3-3 proteins in cerebrospinal fluid provides a sensitive and specific biomarker of neuronal damage associated with Alzheimer’s disease (AD), Creutzfeldt–Jakob disease (CJD), spongiform encephalitis, brain cancers, and stroke. We observed significant enrichment of 14-3-3 paralogs G, S, and Z in human brain aggregates diagnostic of AD. We used intra-aggregate crosslinking to identify 14-3-3 interaction partners, all of which were significantly enriched in AD brain aggregates relative to controls. We screened FDA-approved drugs in silico for structures that could target the 14-3-3G/hexokinase interface, an interaction specific to aggregates and AD. C. elegans possesses only two 14-3-3 orthologs, which bind diverse proteins including DAF-16 (a FOXO transcription factor) and SIR-2.1 (a sensor of nutrients and stress), influencing lifespan. Top drug candidates were tested in C. elegans models of neurodegeneration-associated aggregation and in a human neuroblastoma cell-culture model of AD-like amyloidosis. Several drugs opposed aggregation in all models assessed and rescued behavioral deficits in C. elegans AD-like neuropathy models, suggesting that 14-3-3 proteins are instrumental in aggregate accrual and supporting the advancement of drugs targeting 14-3-3 protein complexes with their partners. MDPI 2022-12-07 /pmc/articles/PMC9779020/ /pubmed/36555098 http://dx.doi.org/10.3390/ijms232415457 Text en © 2022 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 Ganne, Akshatha Balasubramaniam, Meenakshisundaram Mainali, Nirjal Atluri, Paavan Shmookler Reis, Robert J. Ayyadevara, Srinivas Physiological Consequences of Targeting 14-3-3 and Its Interacting Partners in Neurodegenerative Diseases |
title | Physiological Consequences of Targeting 14-3-3 and Its Interacting Partners in Neurodegenerative Diseases |
title_full | Physiological Consequences of Targeting 14-3-3 and Its Interacting Partners in Neurodegenerative Diseases |
title_fullStr | Physiological Consequences of Targeting 14-3-3 and Its Interacting Partners in Neurodegenerative Diseases |
title_full_unstemmed | Physiological Consequences of Targeting 14-3-3 and Its Interacting Partners in Neurodegenerative Diseases |
title_short | Physiological Consequences of Targeting 14-3-3 and Its Interacting Partners in Neurodegenerative Diseases |
title_sort | physiological consequences of targeting 14-3-3 and its interacting partners in neurodegenerative diseases |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9779020/ https://www.ncbi.nlm.nih.gov/pubmed/36555098 http://dx.doi.org/10.3390/ijms232415457 |
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