Despite advances in genomics in recent years, schizophrenia remains one of the most complex challenges of both genetics and neuroscience. The chromosomal abnormality 22q11 deletion syndrome, also known as DiGeorge syndrome, offers a way in, since it is one of the strongest genetic risk factors for schizophrenia.
Out of dozens of genes within the 22q11 deletion, several encode proteins found in mitochondria. A team of Emory scientists, led by cell biologist Victor Faundez, recently analyzed the network of proteins found in human cells, both from individuals affected by 22q11 deletion syndrome and their healthy relatives.
The results are published in Journal of Neuroscience. Note: this is a sprawling paper, involving both proteomics (courtesy of Nick Seyfried, whose Emory epithet is “wizard”) and mutant Drosophila fruit flies. There are four co-first authors: , ,
Mitochondrial proteins are important for keeping cells fueled up and in metabolic balance, but how does altering them affect the brain in a way that leads to schizophrenia? That’s the overall question: how do changes in the miniature power plants within the cell affect synapses, the junctions between cells?
The scientists were focusing on one particular mitochondrial protein, SLC25A1, whose corresponding gene is in the 22q11 deletion. Faundez says that SCL25A1 has been largely ignored by other scientists studying 22q11.
“We think SLC25A1 exerts a powerful influence on the neurodevelopmental phenotypes in 22q11,” he says. “Our main focus forward is going to be the function that mitochondria play in synapse biology.”
SLC25A1 and its interaction partner SLC25A4 pump either citrate (metabolic material) or ATP (cellular energy currency) out of mitochondria to the rest of the cell.
One finding: if you mess with one mitochondrial protein, you mess with dozens. The Emory team found that SLC25A1 is a “principal node” in the network of mitochondrial proteins, and in affected individuals, a large group of its partners have reduced levels.
A limitation is that Faundez and his colleagues were looking at skin fibroblasts — more easily obtained than brain cells. Still, mitochondria are all over the body. Also, they compared their analyses of different families’ cells, and with similar data sets from the brains of genetically altered mice and Drosophila. In fact, the Emory researchers were able to show that reducing the levels of the fly versions of the mitochondrial proteins altered the structure of neuronal synapses and their signaling properties.
For future investigations, Faundez reports that his lab is collaborating with Zhexing Wen to generate human neurons in cell culture from 22q11 patients, derived from iPS cells (induced pluripotent stem