{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:06:03Z","timestamp":1792789563807,"version":"4.5.0"},"reference-count":37,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2022,12,7]],"date-time":"2022-12-07T00:00:00Z","timestamp":1670371200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000738","name":"National Institute on Aging (NIA\/NIH)","doi-asserted-by":"publisher","award":["1R01 AG062254"],"award-info":[{"award-number":["1R01 AG062254"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000738","name":"National Institute on Aging (NIA\/NIH)","doi-asserted-by":"publisher","award":["I01 BX001655"],"award-info":[{"award-number":["I01 BX001655"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000738","name":"National Institute on Aging (NIA\/NIH)","doi-asserted-by":"publisher","award":["IK6 BX004851"],"award-info":[{"award-number":["IK6 BX004851"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"name":"U.S. Dept. of Veteran Affairs","award":["1R01 AG062254"],"award-info":[{"award-number":["1R01 AG062254"]}]},{"name":"U.S. Dept. of Veteran Affairs","award":["I01 BX001655"],"award-info":[{"award-number":["I01 BX001655"]}]},{"name":"U.S. Dept. of Veteran Affairs","award":["IK6 BX004851"],"award-info":[{"award-number":["IK6 BX004851"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The mammalian 14-3-3 family comprises seven intrinsically unstructured, evolutionarily conserved proteins that bind &gt;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\u2019s disease (AD), Creutzfeldt\u2013Jakob 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.<\/jats:p>","DOI":"10.3390\/ijms232415457","type":"journal-article","created":{"date-parts":[[2022,12,7]],"date-time":"2022-12-07T02:49:35Z","timestamp":1670381375000},"page":"15457","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Physiological Consequences of Targeting 14-3-3 and Its Interacting Partners in Neurodegenerative Diseases"],"prefix":"10.3390","volume":"23","author":[{"given":"Akshatha","family":"Ganne","sequence":"first","affiliation":[{"name":"Reynolds Institute on Aging, Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meenakshisundaram","family":"Balasubramaniam","sequence":"additional","affiliation":[{"name":"Reynolds Institute on Aging, Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9679-1174","authenticated-orcid":false,"given":"Nirjal","family":"Mainali","sequence":"additional","affiliation":[{"name":"BioInformatics Program, University of Arkansas at Little Rock and University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paavan","family":"Atluri","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Arkansas, Fayetteville, AR 72701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4691-0734","authenticated-orcid":false,"given":"Robert J.","family":"Shmookler Reis","sequence":"additional","affiliation":[{"name":"Reynolds Institute on Aging, Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"},{"name":"BioInformatics Program, University of Arkansas at Little Rock and University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"},{"name":"Central Arkansas Veterans Healthcare Service, Little Rock, AR 72205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Srinivas","family":"Ayyadevara","sequence":"additional","affiliation":[{"name":"Reynolds Institute on Aging, Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"},{"name":"BioInformatics Program, University of Arkansas at Little Rock and University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"},{"name":"Central Arkansas Veterans Healthcare Service, Little Rock, AR 72205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,7]]},"reference":[{"key":"ref_1","first-page":"4738","article-title":"14-3-3 proteins: An important regulator of autophagy in diseases","volume":"9","author":"Jia","year":"2017","journal-title":"Am. J. Transl. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"500","DOI":"10.5483\/BMBRep.2020.53.10.158","article-title":"Emerging roles of 14-3-3gamma in the brain disorder","volume":"53","author":"Cho","year":"2020","journal-title":"BMB Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5587","DOI":"10.1038\/s41388-018-0348-3","article-title":"The dynamic and stress-adaptive signaling hub of 14-3-3: Emerging mechanisms of regulation and context-dependent protein-protein interactions","volume":"37","author":"Pennington","year":"2018","journal-title":"Oncogene"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/S0014-5793(01)03288-4","article-title":"How do 14-3-3 proteins work?\u2014Gatekeeper phosphorylation and the molecular anvil hypothesis","volume":"513","author":"Yaffe","year":"2002","journal-title":"FEBS Lett."},{"key":"ref_5","first-page":"152","article-title":"14-3-3 proteins in neurological disorders","volume":"3","author":"Foote","year":"2012","journal-title":"Int. J. Biochem. Mol. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"reviews3010.1","DOI":"10.1186\/gb-2002-3-7-reviews3010","article-title":"The 14-3-3s","volume":"3","author":"Ferl","year":"2002","journal-title":"Genome Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3755","DOI":"10.1021\/acs.jmedchem.7b00574","article-title":"Modulators of 14-3-3 Protein-Protein Interactions","volume":"61","author":"Stevers","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/bs.vh.2014.12.006","article-title":"Chapter Seven\u2014Pharmacological Regulation of the Cholesterol Transport Machinery in Steroidogenic Cells of the Testis","volume":"Volume 98","author":"Litwack","year":"2015","journal-title":"Vitamins & Hormones"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/B978-0-444-63945-5.00009-X","article-title":"Sporadic Creutzfeldt-Jakob disease","volume":"153","author":"Zerr","year":"2018","journal-title":"Handb. Clin. Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.3233\/JAD-180514","article-title":"Diffuse Amyloid-beta Plaques, Neurofibrillary Tangles, and the Impact of APOE in Elderly Persons\u2019 Brains Lacking Neuritic Amyloid Plaques","volume":"64","author":"Abner","year":"2018","journal-title":"J. Alzheimers Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3192","DOI":"10.1523\/JNEUROSCI.3769-16.2017","article-title":"Tau and beta-Amyloid Are Associated with Medial Temporal Lobe Structure, Function, and Memory Encoding in Normal Aging","volume":"37","author":"Marks","year":"2017","journal-title":"J. Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1016\/j.bbrc.2016.07.123","article-title":"Amyloid-beta and tau pathology following repetitive mild traumatic brain injury","volume":"483","author":"Edwards","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1016\/j.arcmed.2012.10.012","article-title":"Role of tau protein in neuronal damage in Alzheimer\u2019s disease and Down syndrome","volume":"43","author":"Cardenas","year":"2012","journal-title":"Arch. Med. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1111\/j.1471-4159.2008.05716.x","article-title":"Phosphorylation of tau at Ser214 mediates its interaction with 14-3-3 protein: Implications for the mechanism of tau aggregation","volume":"108","author":"Sadik","year":"2009","journal-title":"J. Neurochem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1111\/acel.12501","article-title":"Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer\u2019s hippocampus from normal controls","volume":"15","author":"Ayyadevara","year":"2016","journal-title":"Aging Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1111\/acel.12296","article-title":"Proteins in aggregates functionally impact multiple neurodegenerative disease models by forming proteasome-blocking complexes","volume":"14","author":"Ayyadevara","year":"2015","journal-title":"Aging Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2794","DOI":"10.3390\/ijms15022794","article-title":"Insight into conformational change for 14-3-3sigma protein by molecular dynamics simulation","volume":"15","author":"Hu","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/j.isci.2019.09.026","article-title":"Aggregate Interactome Based on Protein Cross-linking Interfaces Predicts Drug Targets to Limit Aggregation in Neurodegenerative Diseases","volume":"20","author":"Balasubramaniam","year":"2019","journal-title":"iScience"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"18270","DOI":"10.1074\/jbc.RA118.002121","article-title":"ER stress signaling has an activating transcription factor 6alpha (ATF6)-dependent \u201coff-switch\u201d","volume":"293","author":"Walter","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_20","first-page":"741","article-title":"Coordinate morphological and biochemical interconversion of human neuroblastoma cells","volume":"71","author":"Ross","year":"1983","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"754","DOI":"10.3390\/cells1040754","article-title":"14-3-3 Proteins are Regulators of Autophagy","volume":"1","year":"2012","journal-title":"Cells"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1016\/j.biopsych.2015.02.015","article-title":"Inhibition of 14-3-3 Proteins Leads to Schizophrenia-Related Behavioral Phenotypes and Synaptic Defects in Mice","volume":"78","author":"Foote","year":"2015","journal-title":"Biol. Psychiatry"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1161\/HYPERTENSIONAHA.115.06849","article-title":"Age- and Hypertension-Associated Protein Aggregates in Mouse Heart Have Similar Proteomic Profiles","volume":"67","author":"Ayyadevara","year":"2016","journal-title":"Hypertension"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3486","DOI":"10.18632\/aging.101141","article-title":"Proteins that accumulate with age in human skeletal-muscle aggregates contribute to declines in muscle mass and function in Caenorhabditis elegans","volume":"8","author":"Ayyadevara","year":"2016","journal-title":"Aging"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/s40478-020-01110-5","article-title":"14-3-3 mitigates alpha-synuclein aggregation and toxicity in the in vivo preformed fibril model","volume":"9","author":"Underwood","year":"2021","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1111\/j.1755-5949.2010.00177.x","article-title":"The role of tau in Alzheimer\u2019s disease and related disorders","volume":"17","author":"Medeiros","year":"2011","journal-title":"CNS Neurosci. Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.neulet.2007.11.018","article-title":"14-3-3zeta is indispensable for aggregate formation of polyglutamine-expanded huntingtin protein","volume":"431","author":"Omi","year":"2008","journal-title":"Neurosci. Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1159\/000335805","article-title":"Depletion of 14-3-3 protein exacerbates cardiac oxidative stress, inflammation and remodeling process via modulation of MAPK\/NF-kB signaling pathways after streptozotocin-induced diabetes mellitus","volume":"28","author":"Thandavarayan","year":"2011","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Fan, X., Cui, L., Zeng, Y., Song, W., Gaur, U., and Yang, M. (2019). 14-3-3 Proteins Are on the Crossroads of Cancer, Aging, and Age-Related Neurodegenerative Disease. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20143518"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"564534","DOI":"10.1155\/2013\/564534","article-title":"Neuroprotective function of 14-3-3 proteins in neurodegeneration","volume":"2013","author":"Shimada","year":"2013","journal-title":"BioMed Res. Int."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1002\/1531-8249(199911)46:5<774::AID-ANA14>3.0.CO;2-N","article-title":"Detection of 14-3-3 brain protein in the cerebrospinal fluid of patients with paraneoplastic neurological disorders","volume":"46","author":"Saiz","year":"1999","journal-title":"Ann. Neurol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"310","DOI":"10.3389\/fnmol.2019.00310","article-title":"A Novel Microtubule-Binding Drug Attenuates and Reverses Protein Aggregation in Animal Models of Alzheimer\u2019s Disease","volume":"12","author":"Kakraba","year":"2019","journal-title":"Front. Mol. Neurosci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1089\/ars.2016.6978","article-title":"Aspirin-Mediated Acetylation Protects Against Multiple Neurodegenerative Pathologies by Impeding Protein Aggregation","volume":"27","author":"Ayyadevara","year":"2017","journal-title":"Antioxid. Redox Signal"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1038\/35888","article-title":"Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans","volume":"391","author":"Fire","year":"1998","journal-title":"Nature"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The Protein Data Bank","volume":"28","author":"Berman","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"W174","DOI":"10.1093\/nar\/gkv342","article-title":"I-TASSER server: New development for protein structure and function predictions","volume":"43","author":"Yang","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4939","DOI":"10.1002\/sim.8343","article-title":"The nonparametric Behrens-Fisher problem with dependent replicates","volume":"38","author":"Roy","year":"2019","journal-title":"Stat. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/24\/15457\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:35:27Z","timestamp":1760146527000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/24\/15457"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,7]]},"references-count":37,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["ijms232415457"],"URL":"https:\/\/doi.org\/10.3390\/ijms232415457","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,7]]}}}