November 2016

Cellular Energy Flaws Studied as Contributor to Schizophrenia

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The brain is an energy hog, consuming more energy than any other single organ despite its small size relative to the rest of the body. Scientists are increasingly considering the possibility that subtle defects in energy consumption could help explain some neurological and neuropsychiatric diseases and conditions — and ultimately lead toward identifying better treatments.

“Schizophrenia is a very heterogeneous problem, so you can’t really find just one cause,” said Stewart Anderson, MD, a research psychiatrist at Children’s Hospital of Philadelphia. “Instead, you can try to find common denominators, and one of the common denominators over the years has been that some people with schizophrenia have metabolic problems that you can detect in their blood.”

Dr. Anderson is leading a new study, funded by the National Institute of Mental Health, focused on an underlying cause of some metabolic problems that could relate to the mechanism of disease in schizophrenia, a severe, chronic, often disabling mental health condition that typically emerges in adolescence or young adulthood and involves distorted and confused thoughts and sometimes paranoia and hallucinations.

The idea is that one of the multiple underlying causes of schizophrenia could involve disruptions — even subtle ones — in the power plants of the body’s cells, the mitochondria, and that these disruptions in brain cells could affect brain functions. These bean-shaped organelles have their own DNA that codes for essential genes for making energy, distinct from the DNA in the cell’s nucleus, and their activities are also influenced by hundreds of genes in nuclear DNA. A key leader and founder of the field of mitochondrial medicine, Douglas Wallace, PhD, director of the Center for Mitochondrial and Epigenomic Medicine (CMEM) at CHOP, is a co-investigator with Dr. Anderson on the project.

To find out whether and how genes that control mitochondrial function could influence the development of schizophrenia, the researchers are delving deeper into the genetics of a schizophrenia-associated genetic condition, Chromosome 22q11.2 deletion (22q11.2DS). Six of the 41 genes that are on the segment of DNA lost in this deletion of a segment of nuclear DNA are genes that code for proteins that localize to the cell’s mitochondria. At the same time, about 25 percent of people with this deletion develop schizophrenia, a rate 25 times higher than the one percent incidence in the general population.

“Why are 75 percent of them not developing schizophrenia?” said Dr. Anderson, who is also associate professor of Psychiatry in the Perelman School of Medicine at the University of Pennsylvania. “Our hypothesis is that the deletion itself affects mitochondrial proteins in a minor way that may not cause disease, but in the 25 percent who have schizophrenia, there’s some kind of genetic second hit that’s affecting mitochondrial function enough to push them over a threshold to get sick.”

Dr. Anderson and colleagues are taking two separate approaches to identify whether mitochondrial function follows a pattern that matches this two-hit hypothesis.

The first approach to answering this question uses neurons grown in the lab from induced pluripotent stem cells using samples from individuals with 22q11.2DS with and without schizophrenia, and from healthy controls. By testing these lab-grown neurons for their mitochondrial functions, Dr. Anderson and colleagues hope to determine if the functional level of each group’s mitochondria matches the pattern of their hypothesis: Fully functional in the healthy controls, less functional in those with 22q11.2DS but without schizophrenia, and still even less functional in those with the deletion who do have schizophrenia. In their preliminary experiments to date, they have found evidence that neurons with 22q11.2DS have disrupted mitochondrial function compared to the healthy controls. The experiments comparing neurons from those with and without schizophrenia in combination with 22q11.2DS, and comparing those two groups with healthy controls, will begin this winter.

The second approach focuses on the genetics of mitochondrial function in samples from these three groups. Partnering with CHOP investigators Beverly Emanuel, PhD, a geneticist and professor of Pediatrics at the Perelman School of Medicine at Penn, and Larry Singh, PhD, a computational geneticist in CMEM, the team will use samples from the International 22q11.2 Brain Behavior Consortium, a collaborative international study on which Dr. Emanuel is a co-investigator. They will sequence genes in the mitochondria and in nuclear DNA that affect mitochondrial function to see if the sequences bear out the second-hit hypothesis as a mechanism for schizophrenia cases associated with this chromosomal deletion.

“We hope we can show that, if you have the 22q deletion, you’re more likely to have schizophrenia if you also have a mutation in any one of these thousand other mitochondria-functioning genes,” Dr. Anderson said. “If that’s the case, we can then build an assay to look at whether there is a pattern of mutation that’s predictive of the development of schizophrenia prospectively. We could also use such laboratory assays as drug discovery platforms to see what compounds seem to be effective at restoring mitochondrial function.”

Predicting the onset of schizophrenia in children before they develop symptoms could open up possibilities for prevention, a concept that Dr. Anderson noted is the core of the new Lifespan Brain Institute at CHOP and Penn, which is directed by Raquel Gur, MD, PhD, and encompasses broad collaborations between investigators at CHOP and Penn.

“We know that neuropsychiatric illnesses that present in later childhood, adolescence or adulthood, have pathological antecedents that start way before symptoms begin,” Dr. Anderson said. “Ideally, we’d really like to intercept the pathological process before people get sick, or before they get any sicker than necessary. The institute was designed in order to facilitate interactions between CHOP, where we’re more focused on the child end, and Penn, where they’re more focused on the adult end but including very young adults. Our goal is to learn what is the typical trajectory of brain development and brain function and, by studying children at high genetic risk for developing mental illnesses, how to best identify when that typical trajectory is being derailed. Then we can figure out new approaches for getting the process back on track.”

In addition to these goals to benefit patients with schizophrenia, Dr. Anderson hopes that the mitochondrial genetics portion of the project will provide added insights for individuals with 22q11.2DS about risks for other diseases. The team plans to share this genetic data as a public resource over the next few years, which could lead to future discoveries of mitochondrial genes’ roles in the risk for cardiac and movement disorders in this population.

More broadly, this project is just one of a growing number of efforts to look at the role of mitochondrial bioenergetics in the brain as a mechanism of neurological and psychiatric conditions. Dr. Wallace, a renowned leader and founder of the field of mitochondrial medicine, has long argued that a traditional biomedical approach focused on the organ exhibiting the most prominent symptoms of a disease (such as the brain) overlooks the key role played by systematic bioenergetics in health. Last year, he led a study published in the Proceedings of the National Academy of Sciences (PNAS) showing that small changes in mitochondrial genes had substantial impacts on physiological stress responses in a mouse model. Recently, he was awarded a new NIMH grant to study whether a major contributor to autism spectrum disorder could be the inhibition of interneurons and defects of developmental migration of interneurons caused by partial mitochondrial dysfunction.

“While human differences in behavior and its relation to predisposition to mental illness as well as to a wide variety of pediatric and adult neurological diseases has been the subject of intense investigations for over a century, we still have a rudimentary understanding of the physiological, genetic, and environmental factors that mediate mental health and illness,” Dr. Wallace said after the PNAS paper was published last year. “Our recent papers strongly suggest that by reorienting our investigations from the anatomy of the brain and brain-specific genes to the mitochondria and the bioenergetics genes, we may have a more productive conceptual framework to understand neuropsychiatric disease. If so, this will spawn a whole new generation of neuropsychiatric therapeutics.”

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