Study confirms mitochondrial deficits in children with autism

Children with autism experience deficits in a type of immune cell that protects the body from infection. Called granulocytes, the cells exhibit one-third the capacity to fight infection and protect the body from invasion compared with the same cells in children who are developing normally.

The cells, which circulate in the bloodstream, are less able to deliver crucial infection-fighting oxidative responses to combat invading pathogens because of dysfunction in their tiny energy-generating organelles, the mitochondria.

The study is published online in the journal Pediatrics.

“Granulocytes fight cellular invaders like bacteria and viruses by producing highly reactive oxidants, toxic chemicals that kill microorganisms. Our findings show that in children with severe autism the level of that response was both lower and slower,”  said Eleonora Napoli, lead study author and project scientist in the Department of Molecular Biosciences in the UC Davis School of Veterinary Medicine. “The granulocytes generated less highly reactive oxidants and took longer to produce them.”

The researchers also found that the mitochondria in the granulocytes of children with autism consumed far less oxygen than those of the typically developing children — another sign of decreased mitochondrial function.

Mitochondria are the main intracellular source of oxygen free radicals, which are very reactive and can harm cellular structures and DNA. Cells can repair typical levels of oxidative damage. However, in the children with autism the cells produced more free radicals and were less able to repair the damage, and as a result experienced more oxidative stress. The free radical levels in the blood cells of children with autism were 1 ½ times greater than those without the disorder.

The study was conducted using blood samples of children enrolled in the Childhood Risk of Autism and the Environment (CHARGE) Study and included 10 children with severe autism age 2 to 5 and 10 age-, race- and sex-matched children who were developing typically.

In an earlier study the research team found decreased mitochondrial fortitude in another type of immune cell, the lymphocytes. Together, the findings suggest that deficiencies in the cells’ ability to fuel brain neurons might lead to some of the cognitive impairments associated with autism. Higher levels of free radicals also might contribute to autism severity.

“The response found among granulocytes mirrors earlier results obtained with lymphocytes from children with severe autism, underscoring the cross-talk between energy metabolism and response to oxidative damage,” said Cecilia Giulivi, professor in the Department of Molecular Biosciences in the UC Davis School of Veterinary Medicine and the study’s senior author.

“It also suggests that the immune response seems to be modulated by a nuclear factor named NRF2,” that controls antioxidant response to environmental factors and may hold clues to the gene-environment interaction in autism, Giulivi said.

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Researchers Confirm Multiple Genes Robustly Contribute to Schizophrenia Risk in Replication

Multiple genes contribute to risk for schizophrenia and appear to function in pathways related to transmission of signals in the brain and immunity, according to an international study led by Virginia Commonwealth University School of Pharmacy researchers.

By better understanding the molecular and biological mechanisms involved with schizophrenia, scientists hope to use this new genetic information to one day develop and design drugs that are more efficacious and have fewer side effects.

In a study published online in the April issue of JAMA Psychiatry, the JAMA Network journal, researchers used a comprehensive and unique approach to robustly identify genes and biological processes conferring risk for schizophrenia.

The researchers first used 21,953 subjects to examine over a million genetic markers. They then systematically collected results from other kinds of biological schizophrenia studies and combined all these results using a novel data integration approach.

The most promising genetic markers were tested again in a large collection of families with schizophrenia patients, a design that avoids pitfalls that have plagued genetic studies of schizophrenia in the past. The genes they identified after this comprehensive approach were found to have involvement in brain function, nerve cell development and immune response.

“Now that we have genes that are robustly associated with schizophrenia, we can begin to design much more specific experiments to understand how disruption of these genes may affect brain development and function,” said principal investigator Edwin van den Oord, Ph.D., professor and director of the Center for Biomarker Research and Personalized Medicine in the Department of Pharmacotherapy and Outcomes Science at the VCU School of Pharmacy.

“Also, some of these genes provide excellent targets for the development of new drugs,” he said.

One specific laboratory experiment currently underway at VCU to better understand the function of one of these genes, TCF4, is being led by Joseph McClay, Ph.D., a co-author on the study and assistant professor and laboratory director in the VCU Center for Biomarker Research and Personalized Medicine. TCF4 works by switching on other genes in the brain. McClay and colleagues are conducting a National Institutes of Health-funded study to determine all genes that are under the control of TCF4. By mapping the entire network, they aim to better understand how disruptions to TCF4 increase risk for schizophrenia.

“Our results also suggest that the novel data integration approach used in this study is a promising tool that potentially can be of great value in studies of a large variety of complex genetic disorders,” said lead author Karolina A. Aberg, Ph.D., research assistant professor and laboratory co-director of the Center for Biomarker Research and Personalized Medicine in the VCU School of Pharmacy.

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