A Mutation Linked with Autism Causes Cholinesterase Retention in the Endoplasmic Reticulum

Mark H. Ellisman, Ph.D. and Palmer Taylor, Ph.D.
University of California San Diego
P42ES10337

Background: Autism-spectrum disorders are a group of heterogeneous neuro-developmental syndromes that are characterized by deficits in social behavior and communication. Autism is accompanied frequently by mental retardation but there are individuals with autism-spectrum disorders (e.g. Asperger syndrome) who have normal, and sometimes unusually specialized, cognitive abilities. Currently, there is only very limited information available on the etiology and biological basis of these disorders.

Recent studies have implicated a family of neuronal cell adhesion molecules called neuroligins in autism spectrum disorders. This protein family is encoded by five genes. One mutation in neuroligin 3, an arginine to cysteine substitution, was identified in a set of twins and has been shown to result in the protein being retained within the endoplasmic reticulum (ER) with very little reaching the cell membrane. The small amount of protein that does reach the surface of the cell shows little binding affinity for its partner, β-neurexin, possibly suggesting misfolding of the protein. Misfolded proteins are known to cause ER stress, which has been implicated in a diverse group of human diseases including viral infections, diabetes, neurodegeneration, etc.

Advance: Neuroligin, butyrylcholinesterase, and acetylcholinesterase are members of the α,β-hydrolase fold family of proteins. NIEHS-supported investigators at the University of California San Diego have determined that homologous arginine to cysteine mutations in the two cholinesterases also results in ER retention. This mutation in butyrylcholinesterase is one of the mutations found to give rise to succinylcholine apnea in patients with plasma butyrylcholinesterase deficiency.

Implications: The researchers propose that the mutation impairs processing through the ER and the Golgi apparatus of the cell because of misfolding of the proteins. Accumulation in the ER causes the protein to be more susceptible to proteosomal degradation. The authors speculate that altering intracellular oxidation/reduction parameters may assist in the proper folding of these proteins and their export. This finding could shed light on the molecular causes of autism and other neurological disorders associated with misfolding of proteins.

Citation: De Jaco A, Comoletti D, Kovarik Z, Gaietta G, Radic Z, Lockridge O, Ellisman MH, Taylor P. A mutation linked with autism reveals a common mechanism of endoplasmic reticulum retention for the alpha, beta-hydrolase fold protein family. J Biol Chem. 2006 Apr 7;281(14):9667-76.