Headliners: Autism: Misfolded Protein Presents Potential Molecular Explanationfor Autism Spectrum Disorders

Abstract

Vol. 114, No. 7 EnvironewsOpen AccessHeadliners: Autism: Misfolded Protein Presents Potential Molecular Explanation for Autism Spectrum Disorders Jerry Phelps Jerry Phelps Search for more papers by this author Published:1 July 2006https://doi.org/10.1289/ehp.114-a409AboutSectionsPDF ToolsDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InRedditEmail De Jaco A, Comoletti D, Kovarik Z, Gaietta G, Radiæ Z, Lockridge O, et al. 2006. A mutation linked with autism reveals a common mechanism of endoplasmic reticulum retention for the α,β-hydrolase fold protein family. J Biol Chem 281:9667–9676.Currently, there is only very limited information available on the etiology and biological basis of the autism spectrum disorders, although a mutation in the neuroligin 3 gene has caught researchers’ attention in recent studies. Now NIEHS grantees Mark H. Ellisman and Palmer Taylor at the University of California, San Diego, and their colleagues have determined that homologous mutations in the genes coding the proteins butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) cause defects in protein expression similar to those seen with neuroligin 3, shedding further light on a potential molecular mechanism underlying autism.The neuroligins, BChE, and AChE are members of the α,β-hydrolase fold family of proteins. The neuroligin 3 mutation, an arginine-to-cysteine substitution, was identified in a set of twins and has been shown to result in most of the expressed protein being retained within the endoplasmic reticulum. The small amount of protein that does reach the surface of the cell shows little binding affinity for its partner, β-neurexin, suggesting possible misfolding of the protein. Misfolded proteins are known to cause endoplasmic reticulum stress. This, in turn, can trigger cell death and contribute to human diseases including neurodegeneration, heart disease, and diabetes mellitus.In the current study, the researchers used confocal fluorescence microscopy and analysis of oligosaccharide processing to observe whether an arginine-to-cysteine mutation affected AChE and BChE similarly despite the proteins having differing oligomerizing capacities. By inserting homologous mutations in the AChE and BChE cDNAs, they found that the mutation also resulted in endoplasmic reticulum retention of the two cholinesterases. The proteins were then likely degraded in the proteasome. The authors speculate that altering intracellular oxidation/reduction parameters may assist in the proper folding and export of these proteins.FiguresReferencesRelatedDetails Vol. 114, No. 7 July 2006Metrics About Article Metrics Publication History Originally published1 July 2006Published in print1 July 2006 Financial disclosures License information EHP is an open-access journal published with support from the National Institute of Environmental Health Sciences, National Institutes of Health. All content is public domain unless otherwise noted. Note to readers with disabilities EHP strives to ensure that all journal content is accessible to all readers. However, some figures and Supplemental Material published in EHP articles may not conform to 508 standards due to the complexity of the information being presented. If you need assistance accessing journal content, please contact [email protected]. Our staff will work with you to assess and meet your accessibility needs within 3 working days.