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Solving the Riddle of Schizophrenia, Several Pieces at a Time

solvingtheriddle“A riddle wrapped in a mystery inside an enigma” was how Winston Churchill described Russia’s position at the outset of World War II ­– a statement that still rings true about our understanding of schizophrenia after more than 100 hundred years of research. While hints have appeared from time to time – autoimmunity, brain connectivity, genetics, age of onset – they seem to elude a synthesis that could help us make sense of this devastating psychiatric disorder. Last month, a paper in Nature seems to have broken the tradition of piecemeal science by pulling together several strings into one fascinating peek at the inner workings of genetic mechanisms, brain development, and even animal models to help make sense of the causes of schizophrenia. The riddle starts to meaningfully unwrap.

Location, location, location

The study starts by honing in on chromosome 6, a region long known to be associated with schizophrenia. However, looking at chromosome 6 is like knowing that a person who lives in the U.S. (the brain for schizophrenia) lives in Texas (chromosome 6, in this case). But where in Texas? To find an exact location within that chromosome 6, researchers focused on genetic markers across the major histocompatibility complex (MHC) – an area associated with schizophrenia. Now we are down to an address in Dallas, but where?

To further pinpoint that location, researchers did population-level analysis and found a strong association to a gene encoding complement component 4, known as C4 gene. This gene has two isotypes, A and B, and are associated with a long (L) or short (S) version of a particular human endogenous retroviral insertion (HERV). Now we seem to find a particular street in Dallas, but why is this person living there? How is a complement system gene associated with schizophrenia?

The complement system is part of the immune system response to protect the body from infection, helping antibodies destroy bacteria, for example. This study found that C4A expression is elevated in the brain tissue from patients with schizophrenia. How could the activation of an immune process in the brain be linked to schizophrenia?

It turns out the immune system plays a key role in a process known as “pruning”, which is part of the central nervous system’s normal development. Pruning of synapses and neurons is a key process of brain maturation that in humans extends from adolescence to the third decade of life. Adolescence is the critical time when most people with schizophrenia start to show symptoms of the disease. One hypothesis here is that schizophrenia could be the product of excessive or inappropriate pruning caused by overexpression of the complement in the brain due to specific C4 gene configurations.

Population-level data strengthen the science

The special beauty of this study is using population data to locate the gene – data from more than 65,000 people, using brain tissue biopsies from 700 postmortem brains to look at the expression of these genes, and looking at mouse models to check the effect of these findings. The authors of this recent report are to be commended for using such a multitude of approaches to continue the work of Emil Kraepelin, the father of modern psychiatry, who wrote in his famous textbook in 1899:

“The real nature of dementia praecox [schizophrenia] is totally obscure. The most widely held opinion at present is that we are dealing here with the gradual failure of an inadequate hereditary factor. Like a tree whose roots no longer find nurture in the available soil, so the intellectual powers are said to dwindle once the inadequate heritage no longer permits further development. But very weighty doubts arise against this view. It is incomprehensible why an organism which has in most cases developed healthily and often vigorously should suddenly, and for no particular reason, not only cease to perfect itself but often even sink into a languishing state.”

With the confluence of findings presented in the current paper, we may be able to point some of these particular reasons and start unwrapping this riddle schizophrenia, from the C4 gene, to complement activity and pruning of synapses, to brain development. Kraepelin would be proud.

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