Autism Research Advance - Researchers Reveal Structure of Protein Altered in Autism

The mainstream media, along with neurodiversity and autism bloggers, are circling the flame of the vaccine-autism "trial". At the end of the day, unless some evidence of conspiracy involving suppression of studies documenting a connection is shown, the trial will probably simply confirm the overwhelming medical and scientific community consensus that there is no causal connection. Meanwhile a real scientific research advance is not drawing anywhere near as much attention - the discovery of how particular genetic mutations affect the protein complex implicated in autism spectrum disorders and contribute to the developmental abnormalities found in children with autism.

Researchers reveal structure of protein altered in autism

As a result of mapping the structure of the protein complex implicated in autism spectrum disorders, a research team led by scientists at the University of California, San Diego (UCSD) Skaggs School of Pharmacy and Pharmaceutical Sciences has discovered how particular genetic mutations affect this complex and contribute to the developmental abnormalities found in children with autism. Their work, published as the cover article in the June issue of the journal Structure, should help scientists pinpoint the consequences of other genetic abnormalities associated with the disorder.

“By understanding the three-dimensional structure of the normal protein, researchers can now make predictions about how mutations in the gene affect the structure of the gene product,” said first author Davide Comoletti, Ph.D., UCSD research associate at the Skaggs School of Pharmacy.

Autism spectrum disorders are developmental disabilities that cause impairments in social interaction and communication. Both children and adults with autism typically show difficulties in verbal and non-verbal communication, interpersonal relationships, and leisure or play activities.

Comoletti and colleagues studied the neuroligin family of proteins that are encoded by genes known to be mutated in certain patients with autism. The neuroligins, and their partner proteins, the neurexins, are involved in the junctions, or synapses, through which cells of the nervous system signal to one another and to non-neuronal tissues such as muscle. These structural studies on neuroligins and neurexins represent a major step toward defining the synaptic organization at the molecular level.

“Normally, individual neuroligins are encoded to interact with specific neurexin partners. The two partners are members of distinct families of proteins involved in synaptic adhesions, imparting ‘stickiness’ that enables them to associate so that synapses form and have the capacity for neurotransmission,” said Palmer Taylor, Ph.D., Dean of the Skaggs School, Sandra & Monroe Trout Professor of Pharmacology, and co-principal investigator of the study, along with Jill Trewhella, Ph.D., of the University of Sydney, Australia and University of Utah.

Incorrect partnering that results when a mutant neuroligin fails to properly align at synapses helps explain why the autism spectrum disorders are manifested in subtle behavioral abnormalities that are seen at an early age.

“Abnormal synaptic development in nerve connections is likely to lead to cognitive deficits seen in patients with autism,” said Taylor. He added that synapse formation and maintenance occurs early in development when the infant brain is still plastic and formative. Therefore, by understanding the structural mutations that affect neurotransmission during development, new leads into drug therapies may emerge.

“We really don’t know what causes autism, but this research represents a solid starting point,” said Sarah Dunsmore, Ph.D., program director with the National Institute of General Medical Sciences, part of the National Institutes of Health, which partly supported the study. “The work suggests that genetic mutations that alter the shape or folding of adhesion proteins in the nervous system influence their interactions. This is another example of how research on basic biological questions, such as the three-dimensional structures of proteins in the brain, can yield valuable medical insights.”

Taylor and colleagues have been studying the structure and function of acetylcholinesterase – a structurally related protein that mediates neurotransmission between nerves and between nerve and muscle – for the past 30 years. They began studying the neuroligins because of the similarity in structure and amino acid sequence with acetylcholinesterase. Source : University of California - San Diego

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Synaptic Arrangement of the Neuroligin/β-Neurexin Complex Revealed by X-Ray and Neutron Scattering

Davide Comoletti1, 6, Corresponding Author Contact Information, E-mail The Corresponding Author, Alexander Grishaev2, 6, Andrew E. Whitten3, 4, Igor Tsigelny1, Palmer Taylor1 and Jill Trewhella4, 5
1Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA
2National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, USA
3Bragg Institute, Australian Nuclear Science and Technology Organization, Menai, New South Wales 2234, Australia
4School of Molecular and Microbial Biosciences, University of Sydney, New South Wales 2006, Australia
5Department of Chemistry, University of Utah, Salt Lake City, UT 84112, USA
Received 26 December 2006; revised 13 April 2007; accepted 19 April 2007. Published: June 12, 2007. Available online 12 June 2007.

Summary

Neuroligins are postsynaptic cell-adhesion proteins that associate with their presynaptic partners, the neurexins. Using small-angle X-ray scattering, we determined the shapes of the extracellular region of several neuroligin isoforms in solution. We conclude that the neuroligins dimerize via the characteristic four-helix bundle observed in cholinesterases, and that the connecting sequence between the globular lobes of the dimer and the cell membrane is elongated, projecting away from the dimer interface. X-ray scattering and neutron contrast variation data show that two neurexin monomers, separated by 107 Å, bind at symmetric locations on opposite sides of the long axis of the neuroligin dimer. Using these data, we developed structural models that delineate the spatial arrangements of different neuroligin domains and their partnering molecules. As mutations of neurexin and neuroligin genes appear to be linked to autism, these models provide a structural framework for understanding altered recognition by these proteins in neurodevelopmental disorders.

Author Keywords: MOLNEURO

Structure, Volume 15, Issue 6, 13 June 2007, Pages 693-705