Document Detail


Brainstem deficiency of the 14-3-3 regulator of serotonin synthesis: a proteomics analysis in the sudden infant death syndrome.
MedLine Citation:
PMID:  21976671     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Impaired brainstem responses to homeostatic challenges during sleep may result in the sudden infant death syndrome (SIDS). Previously we reported a deficiency of serotonin (5-HT) and its key biosynthetic enzyme, tryptophan hydroxylase (TPH2), in SIDS infants in the medullary 5-HT system that modulates homeostatic responses during sleep. Yet, the underlying basis of the TPH2 and 5-HT deficiency is unknown. In this study, we tested the hypothesis that proteomics would uncover previously unrecognized abnormal levels of proteins related to TPH2 and 5-HT regulation in SIDS cases compared with controls, which could provide novel insight into the basis of their deficiency. We first performed a discovery proteomic analysis of the gigantocellularis of the medullary 5-HT system in the same data set with deficiencies of TPH2 and 5-HT levels. Analysis in 6 SIDS cases and 4 controls revealed a 42-75% reduction in abundance in 5 of the 6 isoforms identified of the 14-3-3 signal transduction family, which is known to influence TPH2 activity (p < 0.07). These findings were corroborated in an additional SIDS and control sample using an orthogonal MS(E)-based quantitative proteomic strategy. To confirm these proteomics results in a larger data set (38 SIDS, 11 controls), we applied Western blot analysis in the gigantocellularis and found that 4/7 14-3-3 isoforms identified were significantly reduced in SIDS cases (p ≤ 0.02), with a 43% reduction in all 14-3-3 isoforms combined (p < 0.001). Abnormalities in 5-HT and TPH2 levels and 5-HT(1A) receptor binding were associated with the 14-3-3 deficits in the same SIDS cases. These data suggest a potential molecular defect in SIDS related to TPH2 regulation, as 14-3-3 is critical in this process.
Authors:
Kevin G Broadbelt; Keith D Rivera; David S Paterson; Jhodie R Duncan; Felicia L Trachtenberg; Joao A Paulo; Martha D Stapels; Natalia S Borenstein; Richard A Belliveau; Elisabeth A Haas; Christina Stanley; Henry F Krous; Hanno Steen; Hannah C Kinney
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-10-05
Journal Detail:
Title:  Molecular & cellular proteomics : MCP     Volume:  11     ISSN:  1535-9484     ISO Abbreviation:  Mol. Cell Proteomics     Publication Date:  2012 Jan 
Date Detail:
Created Date:  2012-01-12     Completed Date:  2012-05-01     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  101125647     Medline TA:  Mol Cell Proteomics     Country:  United States    
Other Details:
Languages:  eng     Pagination:  M111.009530     Citation Subset:  IM    
Affiliation:
Department of Pathology, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts 02115, USA. kevin.broadbelt@childrens.harvard.edu
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MeSH Terms
Descriptor/Qualifier:
14-3-3 Proteins / deficiency*
Brain Stem / metabolism*
Chromatography, Liquid
Female
Humans
Infant
Infant, Newborn
Male
Mass Spectrometry
Proteomics
Serotonin / deficiency*
Sudden Infant Death*
Tryptophan Hydroxylase / deficiency*
Grant Support
ID/Acronym/Agency:
5 U01 HD045991-06/HD/NICHD NIH HHS; P01 HD036379-11/HD/NICHD NIH HHS; P01-HD036379/HD/NICHD NIH HHS; P30 HD018655-20/HD/NICHD NIH HHS; P30-HD18655/HD/NICHD NIH HHS; R01 HD020991/HD/NICHD NIH HHS; R01-HD020991-24/HD/NICHD NIH HHS; R37 HD020991-14/HD/NICHD NIH HHS; R37-HD20991/HD/NICHD NIH HHS; U01 HD045991-06/HD/NICHD NIH HHS
Chemical
Reg. No./Substance:
0/14-3-3 Proteins; 50-67-9/Serotonin; EC 1.14.16.4/Tryptophan Hydroxylase
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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