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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...

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Autores principales: Ganne, Akshatha, Balasubramaniam, Meenakshisundaram, Mainali, Nirjal, Atluri, Paavan, Shmookler Reis, Robert J., Ayyadevara, Srinivas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
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.
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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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