Schizophrenia, broken-links
Larry H. Bernstein, MD, FCAP, Curator
LPBI
Runs in the Family
http://www.newyorker.com/wp-content/uploads/2016/03/160328_r27877-690.jpg
The author and his father have seen several relatives succumb to mental illness.CREDIT PHOTOGRAPH BY DAYANITA SINGH FOR THE NEW YORKER
In the winter of 2012, I travelled from New Delhi, where I grew up, to Calcutta to visit my cousin Moni. My father accompanied me as a guide and companion, but he was a sullen and brooding presence, lost in a private anguish. He is the youngest of five brothers, and Moni is his firstborn nephew—the eldest brother’s son. Since 2004, Moni, now fifty-two, has been confined to an institution for the mentally ill (a “lunatic home,” as my father calls it), with a diagnosis of schizophrenia. He is kept awash in antipsychotics and sedatives, and an attendant watches, bathes, and feeds him through the day.
My father has never accepted Moni’s diagnosis. Over the years, he has waged a lonely campaign against the psychiatrists charged with his nephew’s care, hoping to convince them that their diagnosis was a colossal error, or that Moni’s broken psyche would somehow mend itself. He has visited the institution in Calcutta twice—once without warning, hoping to see a transformed Moni, living a secretly normal life behind the barred gates. But there was more than just avuncular love at stake for him in these visits. Moni is not the only member of the family with mental illness. Two of my father’s four brothers suffered from various unravellings of the mind. Madness has been among the Mukherjees for generations, and at least part of my father’s reluctance to accept Moni’s diagnosis lies in a grim suspicion that something of the illness may be buried, like toxic waste, in himself.
Rajesh, my father’s third-born brother, had once been the most promising of the Mukherjee boys—the nimblest, the most charismatic, the most admired. But in the summer of 1946, at the age of twenty-two, he began to behave oddly, as if a wire had been tripped in his brain. The most obvious change in his personality was a volatility: good news triggered uncontained outbursts of joy; bad news plunged him into inconsolable desolation. By that winter, the sine curve of Rajesh’s psyche had tightened in its frequency and gained in its amplitude. My father recalls an altered brother: fearful at times, reckless at others, descending and ascending steep slopes of mood, irritable one morning and overjoyed the next. When Rajesh received news of a successful performance on his college exams, he vanished, elated, on a two-night excursion, supposedly “exercising” at a wrestling camp. He was feverish and hallucinating when he returned, and died of pneumonia soon afterward. Only years later, in medical school, did I realize that Rajesh was likely in the throes of an acute manic phase. His mental breakdown was the result of a near-textbook case of bipolar disorder.
Jagu, the fourth-born of my father’s siblings, came to live with us in Delhi in 1975, when I was five years old and he was forty-five. His mind, too, was failing. Tall and rail thin, with a slightly feral look in his eyes and a shock of matted, overgrown hair, he resembled a Bengali Jim Morrison. Unlike Rajesh, whose illness had surfaced in his twenties, Jagu had been troubled from his adolescence. Socially awkward, withdrawn from everyone except my grandmother, he was unable to hold a job or live by himself. By 1975, he had visions, phantasms, and voices in his head that told him what to do. He was still capable of extraordinary bursts of tenderness—when I accidentally smashed a beloved Venetian vase at home, he hid me in his bedclothes and informed my mother that he had “mounds of cash” stashed away, enough to buy “a thousand” replacement vases. But this episode was symptomatic: even his love for me extended the fabric of his psychosis and confabulation.
Unlike Rajesh, Jagu was formally diagnosed. In the late nineteen-seventies, a physician in Delhi examined him and determined that he had schizophrenia. But no medicines were prescribed. Instead, Jagu continued to live at home, half hidden away in my grandmother’s room. (As in many families in India, my grandmother lived with us.) For nearly a decade, she and my father maintained a fragile truce, with Jagu living under her care, eating meals in her room and wearing clothes that she stitched for him. At night, when Jagu was consumed by his fears and fantasies, she put him to bed like a child, with her hand on his forehead. She was his nurse, his housekeeper, his only friend, and, more important, his public defender. When my grandmother died, in 1985, Jagu joined a religious sect in Delhi and disappeared, until his death, a dozen years later.
……
at schizophrenia runs in families was evident even to the person who first defined the illness. In 1911, Eugen Bleuler, a Swiss-German psychiatrist, published a book describing a series of cases of men and women, typically in their teens and early twenties, whose thoughts had begun to tangle and degenerate. “In this malady, the associations lose their continuity,” Bleuler wrote. “The threads between thoughts are torn.” Psychotic visions and paranoid thoughts flashed out of nowhere. Some patients “feel themselves weak, their spirit escapes, they will never survive the day. There is a growth in their heads. Their bones have turned liquid; their hearts have turned into stone. . . . The patient’s wife must not use eggs in cooking, otherwise he will grow feathers.” His patients were often trapped between flickering emotional states, unable to choose between two radically opposed visions, Bleuler noted. “You devil, you angel, you devil, you angel,” one woman said to her lover.
Bleuler tried to find an explanation for the mysterious symptoms, but there was only one seemingly common element: schizophrenic patients tended to have first-degree relatives who were also schizophrenic. He had no tools to understand the mechanism behind the heredity. The word “gene” had been coined just two years before Bleuler published his book. The notion that a mental illness could be carried across generations by unitary, indivisible factors—corpuscles of information threading through families—would have struck most of Bleuler’s contemporaries as mad in its own right. Still, Bleuler was astonishingly prescient about the complex nature of inheritance. “If one is looking for ‘theheredity,’ one can nearly always find it,” he wrote. “We will not be able to do anything about it even later on, unless the single factor of heredity can be broken down into many hereditary factors along specific lines.”
In the nineteen-sixties, Bleuler’s hunch was confirmed by twin studies. Psychiatrists determined that if an identical twin was schizophrenic the other twin had a forty-to-fifty-per-cent chance of developing the disease—fiftyfold higher than the risk in the general population. By the early two-thousands, large population studies had revealed a strong genetic link between schizophrenia and bipolar disorder. Some of the families described in these studies had a crisscrossing history that was achingly similar to my own: one sibling affected with schizophrenia, another with bipolar disorder, and a nephew or niece also schizophrenic.
“The twin studies clarified two important features of schizophrenia and bipolar disorder,” Jeffrey Lieberman, a Columbia University psychiatrist who has studied schizophrenia for thirty years, told me. “First, it was clear that there wasn’t a single gene, but dozens of genes involved in causing schizophrenia—each perhaps exerting a small effect. And, second, even if you inherited the entire set of risk genes, as identical twins do, you still might not develop the disease. Obviously, there were other triggers or instigators involved in releasing the illness.” But while these studies established that schizophrenia had a genetic basis, they revealed nothing about the nature of the genes involved. “For doctors, patients, and families in the schizophrenia community, genetics became the ultimate mystery,” Lieberman said. “If we knew the identity of the genes, we would find the causes, and if we found the causes we could find medicines.”
In 2006, an international consortium of psychiatric geneticists launched a genomic survey of schizophrenia, hoping to advance the search for the implicated genes. With 3,322 patients and 3,587 controls, this was one of the largest and most rigorous such studies in the history of the disease. Researchers scanned through the nearly seven thousand genomes to find variations in gene segments that were correlated with schizophrenia. This strategy, termed an “association study,” does not pinpoint a gene, but it provides a general location where a disease-linked gene may be found, like a treasure map with a large “X” scratched in a corner of the genome.
The results, reported in 2009 (and updated in 2014) in the journal Nature, were a dispiriting validation of Bleuler’s hunch about multiple hereditary factors: more than a hundred independent segments of the genome were associated with schizophrenia. “There are lots of small, common genetic effects, scattered across the genome,” one researcher said. “There are many different biological processes involved.” Some of the putative culprits made biological sense—if dimly. There were genes linked to transmitters that relay messages between neurons, and genes for molecular channels that move electrical signals up and down nerve cells. But by far the most surprising association involved a gene segment on chromosome 6. This region of the genome—termed the MHC region—carries hundreds of genes typically associated with the immune system.
“The MHC-segment finding was so strange and striking that you had to sit up and take notice,” Lieberman told me. “Here was the most definitive evidence that something in the immune system might have something to do with schizophrenia. There had been hints about an immunological association before, but this was impossible to argue with. It raised an endlessly fascinating question: what was the link between immune-response genes and schizophrenia?”
The Rogue Immune Cells That Wreck the Brain
Beth Stevens thinks she has solved a mystery behind brain disorders such as Alzheimer’s and schizophrenia.
by Adam Piore April 4, 2016 https://www.technologyreview.com/s/601137/the-rogue-immune-cells-that-wreck-the-brain/
In the first years of her career in brain research, Beth Stevens thought of microglia with annoyance if she thought of them at all. When she gazed into a microscope and saw these ubiquitous cells with their spidery tentacles, she did what most neuroscientists had been doing for generations: she looked right past them and focused on the rest of the brain tissue, just as you might look through specks of dirt on a windshield.
“What are they doing there?” she thought. “They’re in the way.’”
Stevens never would have guessed that just a few years later, she would be running a laboratory at Harvard and Boston’s Children’s Hospital devoted to the study of these obscure little clumps. Or that she would be arguing in the world’s top scientific journals that microglia might hold the key to understanding not just normal brain development but also what causes Alzheimer’s, Huntington’s, autism, schizophrenia, and other intractable brain disorders.
Microglia are part of a larger class of cells—known collectively as glia—that carry out an array of functions in the brain, guiding its development and serving as its immune system by gobbling up diseased or damaged cells and carting away debris. Along with her frequent collaborator and mentor, Stanford biologist Ben Barres, and a growing cadre of other scientists, Stevens, 45, is showing that these long-overlooked cells are more than mere support workers for the neurons they surround. Her work has raised a provocative suggestion: that brain disorders could somehow be triggered by our own bodily defenses gone bad.
A type of glial cell known as an oligodendrocyte
In one groundbreaking paper, in January, Stevens and researchers at the Broad Institute of MIT and Harvard showed that aberrant microglia might play a role in schizophrenia—causing or at least contributing to the massive cell loss that can leave people with devastating cognitive defects. Crucially, the researchers pointed to a chemical pathway that might be targeted to slow or stop the disease. Last week, Stevens and other researchers published a similar finding for Alzheimer’s.
This might be just the beginning. Stevens is also exploring the connection between these tiny structures and other neurological diseases—work that earned her a $625,000 MacArthur Foundation “genius” grant last September.
All of this raises intriguing questions. Is it possible that many common brain disorders, despite their wide-ranging symptoms, are caused or at least worsened by the same culprit, a component of the immune system? If so, could many of these disorders be treated in a similar way—by stopping these rogue cells?
Sekar A,
Bialas AR,
de Rivera H,
Davis A,
Hammond TR,
Kamitaki N,
Tooley K,
Presumey J,
Baum M,
Van Doren V,
Genovese G,
Rose SA,
Handsaker RE;
Schizophrenia Working Group of the Psychiatric Genomics Consortium,
Daly MJ,
Carroll MC,
Stevens B,
McCarroll SA.
Collaborators (307)
Schizophrenia is a heritable brain illness with unknown pathogenic mechanisms. Schizophrenia’s strongest genetic association at a population level involves variation in the major histocompatibility complex (MHC) locus, but the genes and molecular mechanisms accounting for this have been challenging to identify. Here we show that this association arises in part from many structurally diverse alleles of the complement component 4 (C4) genes. We found that these alleles generated widely varying levels of C4A and C4B expression in the brain, with each common C4 allele associating with schizophrenia in proportion to its tendency to generate greater expression of C4A. Human C4 protein localized to neuronal synapses, dendrites, axons, and cell bodies. In mice, C4 mediated synapse elimination during postnatal development. These results implicate excessive complement activity in the development of schizophrenia and may help explain the reduced numbers of synapses in the brains of individuals with schizophrenia.
Synapse loss in Alzheimer’s disease (AD) correlates with cognitive decline. Involvement of microglia and complement in AD has been attributed to neuroinflammation, prominent late in disease. Here we show in mouse models that complement and microglia mediate synaptic loss early in AD. C1q, the initiating protein of the classical complement cascade, is increased and associated with synapses before overt plaque deposition. Inhibition of C1q, C3 or the microglial complement receptor CR3, reduces the number of phagocytic microglia as well as the extent of early synapse loss. C1q is necessary for the toxic effects of soluble β-amyloid (Aβ) oligomers on synapses and hippocampal long-term potentiation (LTP). Finally, microglia in adult brains engulf synaptic material in a CR3-dependent process when exposed to soluble Aβ oligomers. Together, these findings suggest that the complement-dependent pathway and microglia that prune excess synapses in development are inappropriately activated and mediate synapse loss in AD.
Genome-wide association studies (GWAS) implicate microglia and complement-related pathways in AD (
1). Previous research has demonstrated both beneficial and detrimental roles of complement and microglia in plaque-related neuropathology (
2,
3); however, their roles in synapse loss, a major pathological correlate of cognitive decline in AD (
4), remain to be identified. Emerging research implicates microglia and immune-related mechanisms in brain wiring in the healthy brain (
1). During development, C1q and C3 localize to synapses and mediate synapse elimination by phagocytic microglia (
5–
7). We hypothesized that this normal developmental synaptic pruning pathway is activated early in the AD brain and mediates synapse loss.
Complex machinery
It’s not surprising that scientists for years have ignored microglia and other glial cells in favor of neurons. Neurons that fire together allow us to think, breathe, and move. We see, hear, and feel using neurons, and we form memories and associations when the connections between different neurons strengthen at the junctions between them, known as synapses. Many neuroscientists argue that neurons create our very consciousness.
Glia, on the other hand, have always been considered less important and interesting. They have pedestrian duties such as supplying nutrients and oxygen to neurons, as well as mopping up stray chemicals and carting away the garbage.
Scientists have known about glia for some time. In the 1800s, the pathologist Rudolf Virchow noted the presence of small round cells packing the spaces between neurons and named them “nervenkitt” or “neuroglia,” which can be translated as nerve putty or glue. One variety of these cells, known as astrocytes, was defined in 1893. And then in the 1920s, the Spanish scientist Pio del Río Hortega developed novel ways of staining cells taken from the brain. This led him to identify and name two more types of glial cells, including microglia, which are far smaller than the others and are characterized by their spidery shape and multiple branches. It is only when the brain is damaged in adulthood, he suggested, that microglia spring to life—rushing to the injury, where it was thought they helped clean up the area by eating damaged and dead cells. Astrocytes often appeared on the scene as well; it was thought that they created scar tissue.
This emergency convergence of microglia and astrocytes was dubbed “gliosis,” and by the time Ben Barres entered medical school in the late 1970s, it was well established as a hallmark of neurodegenerative diseases, infection, and a wide array of other medical conditions. But no one seemed to understand why it occurred. That intrigued Barres, then a neurologist in training, who saw it every time he looked under a microscope at neural tissue in distress. “It was just really fascinating,” he says. “The great mystery was: what is the point of this gliosis? Is it good? Is it bad? Is it driving the disease process, or is it trying to repair the injured brain?”
Barres began looking for the answer. He learned how to grow glial cells in a dish and apply a new recording technique to them. He could measure their electrical qualities, which determine the biochemical signaling that all brain cells use to communicate and coördinate activity.
“From the second I started recording the glial cells, I thought ‘Oh, my God!’” Barres recalls. The electrical activity was more dynamic and complex than anyone had thought. These strange electrical properties could be explained only if the glial cells were attuned to the conditions around them, and to the signals released from nearby neurons. Barres’s glial cells, in other words, had all the machinery necessary to engage in a complex dialogue with neurons, and presumably to respond to different kinds of conditions in the brain.
Why would they need this machinery, though, if they were simply involved in cleaning up dead cells? What could they possibly be doing? It turns out that in the absence of chemicals released by glia, the neurons committed the biochemical version of suicide. Barres also showed that the astrocytes appeared to play a crucial role in forming synapses, the microscopic connections between neurons that encode memory. In isolation, neurons were capable of forming the spiny appendages necessary to reach the synapses. But without astrocytes, they were incapable of connecting to one another.
Hardly anyone believed him. When he was a young faculty member at Stanford in the 1990s, one of his grant applications to the National Institutes of Health was rejected seven times. “Reviewers kept saying, ‘Nah, there’s no way glia could be doing this,’” Barres recalls. “And even after we published two papers in Science showing that [astrocytes] had profound, almost all-or-nothing effects in controlling synapses’ formation or synapse activity, I still couldn’t get funded! I think it’s still hard to get people to think about glia as doing anything active in the nervous system.”
Marked for elimination
Beth Stevens came to study glia by accident. After graduating from Northeastern University in 1993, she followed her future husband to Washington, D.C., where he had gotten work in the U.S. Senate. Stevens had been pre-med in college and hoped to work in a lab at the National Institutes of Health. But with no previous research experience, she was soundly rebuffed. So she took a job waiting tables at a Chili’s restaurant in nearby Rockville, Maryland, and showed up at NIH with her résumé every week.
After a few months, Stevens received a call from a researcher named Doug Fields, who needed help in his lab. Fields was studying the intricacies of the process in which neurons become insulated in a coating called myelin. That insulation is essential for the transmission of electrical impulses.
As Stevens spent the following years pursuing a PhD at the University of Maryland, she was intrigued by the role that glial cells played in insulating neurons. Along the way, she became familiar with other insights into glial cells that were beginning to emerge, especially from the lab of Ben Barres. Which is why, soon after completing her PhD in 2003, Stevens found herself a postdoc in Barres’s lab at Stanford, about to make a crucial discovery.
Barres’s group had begun to identify the specific compounds astrocytes secreted that seemed to cause neurons to grow synapses. And eventually, they noticed that these compounds also stimulated production of a protein called C1q.
Conventional wisdom held that C1q was activated only in sick cells—the protein marked them to be eaten up by immune cells—and only outside the brain. But Barres had found it in the brain. And it was in healthy neurons that were arguably at their most robust stage: in early development. What was the C1q protein doing there?
https://d267cvn3rvuq91.cloudfront.net/i/images/glia33.jpg?sw=590&cx=0&cy=0&cw=2106&ch=2106
A stained astrocyte.
The answer lies in the fact that marking cells for elimination is not something that happens only in diseased brains; it is also essential for development. As brains develop, their neurons form far more synaptic connections than they will eventually need. Only the ones that are used are allowed to remain. This pruning allows for the most efficient flow of neural transmissions in the brain, removing noise that might muddy the signal.
But it was unknown how exactly the process worked. Was it possible that C1q helped signal the brain to prune unused synapses? Stevens focused her postdoctoral research on finding out. “We could have been completely wrong,” she recalls. “But we went for it.”
It paid off. In a 2007 paper, Barres and Stevens showed that C1q indeed plays a role in eliminating unneeded neurons in the developing brain. And they found that the protein is virtually absent in healthy adult neurons.
Now the scientists faced a new puzzle. Does C1q show up in brain diseases because the same mechanism involved in pruning a developing brain later goes awry? Indeed, evidence was already growing that one of the earliest events in neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s was significant loss of synapses.
When Stevens and Barres examined mice bred to develop glaucoma, a neurodegenerative disease that kills neurons in the optic system, they found that C1q appeared long before any other detectable sign that the disease was taking hold. It cropped up even before the cells started dying.
This suggested the immune cells might in fact cause the disease, or at the very least accelerate it. And that offered an intriguing possibility: that something could be made to halt the process. Barres founded a company, Annexon Biosciences, to develop drugs that could block C1q. Last week’s paper published by Barres, Stevens, and other researchers shows that a compound being tested by Annexon appears to be able to prevent the onset of Alzheimer’s in mice bred to develop the disease. Now the company hopes to test it in humans in the next two years.
Paths to treatments
To better understand the process that C1q helps trigger, Stevens and Barres wanted to figure out what actually plays the role of Pac-Man, eating up the synapses marked for death. It was well known that white blood cells known as macrophages gobbled up diseased cells and foreign invaders in the rest of the body. But macrophages are not usually present in the brain. For their theory to work, there had to be some other mechanism. And further research has shown that the cells doing the eating even in healthy brains are those mysterious clusters of material that Beth Stevens, for years, had been gazing right past in the microscope—the microglia that Río Hortega identified almost 100 years ago.
Now Stevens’s lab at Harvard, which she opened in 2008, devotes half its efforts to figuring out what microglia are doing and what causes them to do it. These cells, it turns out, appear in the mouse embryo at day eight, before any other brain cell, which suggests they might help guide the rest of brain development—and could contribute to any number of neurodevelopmental diseases when they go wrong.
Meanwhile, she is also expanding her study of the way different substances determine what happens in the brain. C1q is actually just the first in a series of proteins that accumulate on synapses marked for elimination. Stevens has begun to uncover evidence that there is a wide array of protective “don’t eat me” molecules too. It’s the balance between all these cues that regulates whether microglia are summoned to destroy synapses. Problems in any one could, conceivably, mess up the system.
Evidence is now growing that microglia are involved in several neurodevelopmental and psychiatric problems. The potential link to schizophrenia that was revealed in January emerged after researchers at the Broad Institute, led by Steven McCarroll and a graduate student named Aswin Sekar, followed a trail of genetic clues that led them directly to Stevens’s work. In 2009, three consortia from around the globe had published papers comparing DNA in people with and without schizophrenia. It was Sekar who identified a possible pattern: the more a specific type of protein was present in synapses, the higher the risk of developing the disease. The protein, C4, was closely related to C1q, the one first identified in the brain by Stevens and Barres.
McCarroll knew that schizophrenia strikes in late adolescence and early adulthood, a time when brain circuits in the prefrontal cortex undergo extensive pruning. Others had found that areas of the prefrontal cortex are among those most ravaged by the disease, which leads to massive synapse loss. Could it be that over-pruning by rogue microglia is part of what causes schizophrenia?
To find out, Sekar and McCarroll got in touch with Stevens, and the two labs began to hold joint weekly meetings. They soon demonstrated that C4 also had a role in pruning synapses in the brains of young mice, suggesting that excessive levels of the protein could indeed lead to over-pruning—and to the thinning out of brain tissue that appears to occur as symptoms such as psychotic episodes grow worse.
If the brain damage seen in Parkinson’s and Alzheimer’s stems from over-pruning that might begin early in life, why don’t symptoms of those diseases show up until later? Barres thinks he knows. He notes that the brain can normally compensate for injury by rewiring itself and generating new synapses. It also contains a lot of redundancy. That would explain why patients with Parkinson’s disease don’t show discernible symptoms until they have lost 90 percent of the neurons that produce dopamine.
It also might mean that subtle symptoms could in fact be detected much earlier. Barres points to a study of nuns published in 2000. When researchers analyzed essays the nuns had written upon entering their convents decades before, they found that women who went on to develop Alzheimer’s had shown less “idea density” even in their 20s. “I think the implication of that is they could be lifelong diseases,” Barres says. “The disease process could be going on for decades and the brain is just compensating, rewiring, making new synapses.” At some point, the microglia are triggered to remove too many cells, Barres argues, and the symptoms of the disease begin to manifest fully.
Turning this insight into a treatment is far from straightforward, because much remains unclear. Perhaps an overly aggressive response from microglia is determined by some combination of genetic variants not shared by everyone. Stevens also notes that diseases like schizophrenia are not caused by one mutation; rather, a wide array of mutations with small effects cause problems when they act in concert. The genes that control the production of C4 and other immune-system proteins may be only part of the story. That may explain why not everyone who has a C4 mutation will go on to develop schizophrenia.
Nonetheless, if Barres and Stevens are right that the immune system is a common mechanism behind devastating brain disorders, that in itself is a fundamental breakthrough. Because we have not known the mechanisms that trigger such diseases, medical researchers have been able only to alleviate the symptoms rather than attack the causes. There are no drugs available to halt or even slow neurodegeneration in diseases like Alzheimer’s. Some drugs elevate neurotransmitters in ways that briefly make it easier for individuals with dementia to form new synaptic connections, but they don’t reduce the rate at which existing synapses are destroyed. Similarly, there are no treatments that tackle the causes of autism or schizophrenia. Even slowing the progress of these disorders would be a major advance. We might finally go after diseases that have run unchecked for generations.
“We’re a ways away from a cure,” Stevens says. “But we definitely have a path forward.”
Adam Piore is a freelance writer who wrote “A Shocking Way to Fix the Brain” in November/December 2015.
Int Immunopharmacol. 2001 Mar;1(3):365-92.
Genetic, structural and functional diversities of human complement components C4A and C4B and their mouse homologues, Slp and C4.
Blanchong CA1, Chung EK, Rupert KL, Yang Y, Yang Z, Zhou B, Moulds JM, Yu CY.
Author information
Abstract
The complement protein C4 is a non-enzymatic component of the C3 and C5 convertases and thus essential for the propagation of the classical complement pathway. The covalent binding of C4 to immunoglobulins and immune complexes (IC) also enhances the solubilization of immune aggregates, and the clearance of IC through complement receptor one (CR1) on erythrocytes. Human C4 is the most polymorphic protein of the complement system. In this review, we summarize the current concepts on the 1-2-3 loci model of C4A and C4B genes in the population, factors affecting the expression levels of C4 transcripts and proteins, and the structural, functional and serological diversities of the C4A and C4B proteins. The diversities and polymorphisms of the mouse homologues Slp and C4 proteins are described and contrasted with their human homologues. The human C4 genes are located in the MHC class III region on chromosome 6. Each human C4 gene consists of 41 exons coding for a 5.4-kb transcript. The long gene is 20.6 kb and the short gene is 14.2 kb. In the Caucasian population 55% of the MHC haplotypes have the 2-locus, C4A-C4B configurations and 45% have an unequal number of C4A and C4B genes. Moreover, three-quarters of C4 genes harbor the 6.4 kb endogenous retrovirus HERV-K(C4) in the intron 9 of the long genes. Duplication of a C4 gene always concurs with its adjacent genes RP, CYP21 and TNX, which together form a genetic unit termed an RCCX module. Monomodular, bimodular and trimodular RCCX structures with 1, 2 and 3 complement C4 genes have frequencies of 17%, 69% and 14%, respectively. Partial deficiencies of C4A and C4B, primarily due to the presence of monomodular haplotypes and homo-expression of C4A proteins from bimodular structures, have a combined frequency of 31.6%. Multiple structural isoforms of each C4A and C4B allotype exist in the circulation because of the imperfect and incomplete proteolytic processing of the precursor protein to form the beta-alpha-gamma structures. Immunofixation experiments of C4A and C4B demonstrate > 41 allotypes in the two classes of proteins. A compilation of polymorphic sites from limited C4 sequences revealed the presence of 24 polymophic residues, mostly clustered C-terminal to the thioester bond within the C4d region of the alpha-chain. The covalent binding affinities of the thioester carbonyl group of C4A and C4B appear to be modulated by four isotypic residues at positions 1101, 1102, 1105 and 1106. Site directed mutagenesis experiments revealed that D1106 is responsible for the effective binding of C4A to form amide bonds with immune aggregates or protein antigens, and H1106 of C4B catalyzes the transacylation of the thioester carbonyl group to form ester bonds with carbohydrate antigens. The expression of C4 is inducible or enhanced by gamma-interferon. The liver is the main organ that synthesizes and secretes C4A and C4B to the circulation but there are many extra-hepatic sites producing moderate quantities of C4 for local defense. The plasma protein levels of C4A and C4B are mainly determined by the corresponding gene dosage. However, C4B proteins encoded by monomodular short genes may have relatively higher concentrations than those from long C4A genes. The 5′ regulatory sequence of a C4 gene contains a Spl site, three E-boxes but no TATA box. The sequences beyond–1524 nt may be completely different as the C4 genes at RCCX module I have RPI-specific sequences, while those at Modules II, III and IV have TNXA-specific sequences. The remarkable genetic diversity of human C4A and C4B probably promotes the exchange of genetic information to create and maintain the quantitative and qualitative variations of C4A and C4B proteins in the population, as driven by the selection pressure against a great variety of microbes. An undesirable accompanying byproduct of this phenomenon is the inherent deleterious recombinations among the RCCX constituents leading to autoimmune and genetic disorders.
C4A isotype is responsible for effective binding to form amide bonds with immune aggregates or protein antigens, while C4B isotype catalyzes the transacylation of the thioester carbonyl group to form ester bonds with carbohydrate antigens.
Derived from proteolytic degradation of complement C4, C4a anaphylatoxin is a mediator of local inflammatory process.
Schizophrenia and the Synapse
Genetic evidence suggests that overactive synaptic pruning drives development of schizophrenia.
By Ruth Williams | January 27, 2016
http://www.the-scientist.com/?articles.view/articleNo/45189/title/Schizophrenia-and-the-Synapse/
Compared to the brains of healthy individuals, those of people with schizophrenia have higher expression of a gene called C4, according to a paper published inNature today (January 27). The gene encodes an immune protein that moonlights in the brain as an eradicator of unwanted neural connections (synapses). The findings, which suggest increased synaptic pruning is a feature of the disease, are a direct extension of genome-wide association studies (GWASs) that pointed to the major histocompatibility (MHC) locus as a key region associated with schizophrenia risk.
“The MHC [locus] is the first and the strongest genetic association for schizophrenia, but many people have said this finding is not useful,” said psychiatric geneticist Patrick Sullivan of the University of North Carolina School of Medicine who was not involved in the study. “The value of [the present study is] to show that not only is it useful, but it opens up new and extremely interesting ideas about the biology and therapeutics of schizophrenia.”
Schizophrenia has a strong genetic component—it runs in families—yet, because of the complex nature of the condition, no specific genes or mutations have been identified. The pathological processes driving the disease remain a mystery.
Researchers have turned to GWASs in the hope of finding specific genetic variations associated with schizophrenia, but even these have not provided clear candidates.
“There are some instances where genome-wide association will literally hit one base [in the DNA],” explained Sullivan. While a 2014 schizophrenia GWAS highlighted the MHC locus on chromosome 6 as a strong risk area, the association spanned hundreds of possible genes and did not reveal specific nucleotide changes. In short, any hope of pinpointing the MHC association was going to be “really challenging,” said geneticist Steve McCarroll of Harvard who led the new study.
Nevertheless, McCarroll and colleagues zeroed in on the particular region of the MHC with the highest GWAS score—the C4 gene—and set about examining how the area’s structural architecture varied in patients and healthy people.
The C4 gene can exist in multiple copies (from one to four) on each copy of chromosome 6, and has four different forms: C4A-short, C4B-short, C4A-long, and C4B-long. The researchers first examined the “structural alleles” of the C4 locus—that is, the combinations and copy numbers of the different C4 forms—in healthy individuals. They then examined how these structural alleles related to expression of both C4Aand C4B messenger RNAs (mRNAs) in postmortem brain tissues.
…………..
Schizophrenia risk from complex variation of complement component 4
Aswin Sekar, Allison R. Bialas, Heather de Rivera, …, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Mark J. Daly, Michael C. Carroll, Beth Stevens & Steven A. McCarroll
Nature (11 Feb 2016); 530: 177–183 http://dx.doi.org:/10.1038/nature16549
Schizophrenia is a heritable brain illness with unknown pathogenic mechanisms. Schizophrenia’s strongest genetic association at a population level involves variation in the major histocompatibility complex (MHC) locus, but the genes and molecular mechanisms accounting for this have been challenging to identify. Here we show that this association arises in part from many structurally diverse alleles of the complement component 4 (C4) genes. We found that these alleles generated widely varying levels of C4A and C4B expression in the brain, with each common C4 allele associating with schizophrenia in proportion to its tendency to generate greater expression of C4A. Human C4 protein localized to neuronal synapses, dendrites, axons, and cell bodies. In mice, C4 mediated synapse elimination during postnatal development. These results implicate excessive complement activity in the development of schizophrenia and may help explain the reduced numbers of synapses in the brains of individuals with schizophrenia.
- Cannon, T. D. et al. Cortex mapping reveals regionally specific patterns of genetic and disease-specific gray-matter deficits in twins discordant for schizophrenia. Proc. Natl Acad. Sci. USA 99, 3228–3233 (2002)
- Cannon, T. D. et al. Progressive reduction in cortical thickness as psychosis develops: a multisite longitudinal neuroimaging study of youth at elevated clinical risk. Biol. Psychiatry 77,147–157 (2015)
- Garey, L. J. et al. Reduced dendritic spine density on cerebral cortical pyramidal neurons in schizophrenia. J. Neurol. Neurosurg. Psychiatry 65, 446–453 (1998)
- Glantz, L. A. & Lewis, D. A. Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch. Gen. Psychiatry 57, 65–73 (2000)
- Glausier, J. R. & Lewis, D. A. Dendritic spine pathology in schizophrenia. Neuroscience 251,90–107 (2013)
- Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421–427 (2014)
- Shi, J. et al. Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature 460, 753–757 (2009)
- Stefansson, H. et al. Common variants conferring risk of schizophrenia. Nature 460,744–747 (2009)
- International Schizophrenia Consortium et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748–752 (2009)
- Schizophrenia Psychiatric Genome-Wide Association Study Consortium. Genome-wide association study identifies five new schizophrenia loci. Nature Genet . 43, 969–976 (2011)
The strongest genetic association found in schizophrenia is its association to genetic markers across the major histocompatibility complex (MHC) locus, first described in three Nature papers in 2009. …
Schizophrenia: From genetics to physiology at last
Ryan S. Dhindsa & David B. Goldstein
Nature (11 Feb 2016); 530:162–163 http://dx.doi.org:/10.1038/nature16874
- Schizophrenia Working Group of the Psychiatric Genomics Consortium. Nature511,421–427 (2014).
- Stevens, B. et al. Cell131, 1164–1178 (2007).
- Cannon, T. D. et al. Psychiatry77, 147–157 (2015).
- Glausier, J. R. & Lewis, D. A. Neuroscience251, 90–107 (2013).
- Glantz, L. A. & Lewis, D. A. Gen. Psychiatry57, 65–73 (2000).
Jianxin Shi1, et al. Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature 460, 753-757 (6 August 2009) | doi:10.1038/nature08192; Received 29 May 2009; Accepted 10 June 2009; Published online 1 July 2009; Corrected 6 August 2009
Schizophrenia, a devastating psychiatric disorder, has a prevalence of 0.5–1%, with high heritability (80–85%) and complex transmission1. Recent studies implicate rare, large, high-penetrance copy number variants in some cases2, but the genes or biological mechanisms that underlie susceptibility are not known. Here we show that schizophrenia is significantly associated with single nucleotide polymorphisms (SNPs) in the extended major histocompatibility complex region on chromosome 6. We carried out a genome-wide association study of common SNPs in the Molecular Genetics of Schizophrenia (MGS) case-control sample, and then a meta-analysis of data from the MGS, International Schizophrenia Consortium and SGENE data sets. No MGS finding achieved genome-wide statistical significance. In the meta-analysis of European-ancestry subjects (8,008 cases, 19,077 controls), significant association with schizophrenia was observed in a region of linkage disequilibrium on chromosome 6p22.1 (P = 9.54 × 10-9). This region includes a histone gene cluster and several immunity-related genes—possibly implicating aetiological mechanisms involving chromatin modification, transcriptional regulation, autoimmunity and/or infection. These results demonstrate that common schizophrenia susceptibility alleles can be detected. The characterization of these signals will suggest important directions for research on susceptibility mechanisms.
Editor’s Summary 6 August 2009
Schizophrenia risk: link to chromosome 6p22.1
A genome-wide association study using the Molecular Genetics of Schizophrenia case-control data set, followed by a meta-analysis that included over 8,000 cases and 19,000 controls, revealed that while common genetic variation that underlies risk to schizophrenia can be identified, there probably are few or no single common loci with large effects. The common variants identified here lie on chromosome 6p22.1 in a region that includes a histone gene cluster and several genes implicated in immunity.
Letter
Hreinn Stefansson1,48, et al. Common variants conferring risk of schizophrenia.
Nature 460, 744-747 (6 August 2009) | doi:10.1038/nature08186; Received 16 March 2009; Accepted 5 June 2009; Published online 1 July 2009
Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is that its genetic basis does not necessarily conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders1, 2, 3. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the ‘genomic disorders’, have not yet been characterized4. Single nucleotide polymorphism (SNP)-based genome-wide association studies with the potential to implicate individual genes in complex diseases may reveal underlying biological pathways. Here we combined SNP data from several large genome-wide scans and followed up the most significant association signals. We found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition.
Letter
The International Schizophrenia Consortium. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748-752 (6 August 2009) | doi:10.1038/nature08185; Received 11 February 2009; Accepted 8 June 2009; Published online 1 July 2009; Corrected 6 August 2009
Schizophrenia is a severe mental disorder with a lifetime risk of about 1%, characterized by hallucinations, delusions and cognitive deficits, with heritability estimated at up to 80%1, 2. We performed a genome-wide association study of 3,322 European individuals with schizophrenia and 3,587 controls. Here we show, using two analytic approaches, the extent to which common genetic variation underlies the risk of schizophrenia. First, we implicate the major histocompatibility complex. Second, we provide molecular genetic evidence for a substantial polygenic component to the risk of schizophrenia involving thousands of common alleles of very small effect. We show that this component also contributes to the risk of bipolar disorder, but not to several non-psychiatric diseases.
The Psychiatric GWAS Consortium Steering Committee. A framework for interpreting genome-wide association studies of psychiatric disorders. Molecular Psychiatry (2009) 14, 10–17; doi:10.1038/mp.2008.126; published online 11 November 2008
Genome-wide association studies (GWAS) have yielded a plethora of new findings in the past 3 years. By early 2009, GWAS on 47 samples of subjects with attention-deficit hyperactivity disorder, autism, bipolar disorder, major depressive disorder and schizophrenia will be completed. Taken together, these GWAS constitute the largest biological experiment ever conducted in psychiatry (59 000 independent cases and controls, 7700 family trios and >40 billion genotypes). We know that GWAS can work, and the question now is whether it will work for psychiatric disorders. In this review, we describe these studies, the Psychiatric GWAS Consortium for meta-analyses of these data, and provide a logical framework for interpretation of some of the conceivable outcomes.
Keywords: genome-wide association, attention-deficit hyperactivity disorder, autism, bipolar disorder, major depressive disorder, schizophrenia
The purpose of this article is to consider the ‘big picture’ and to provide a logical framework for the possible outcomes of these studies. This is not a review of GWAS per se as many excellent reviews of this technically and statistically intricate methodological approach are available.7, 8, 9, 10, 11, 12 This is also not a review of the advantages and disadvantages of different study designs and sampling strategies for the dissection of complex psychiatric traits. We would like to consider how the dozens of GWAS papers that will soon be in the literature can be synthesized: what can integrated mega-analyses (meta-analysis is based on summary data (for example, odds ratios) from all available studies whereas ‘mega-analysis’ uses individual-level genotype and phenotype data) of all available GWAS data tell us about the etiology of these psychiatric disorders? This is an exceptional opportunity as positive or negative results will enable us to learn hard facts about these critically important psychiatric disorders. We suggest that it is not a matter of ‘success versus failure’ or ‘optimism versus pessimism’ but rather an opportunity for systematic and logical approaches to empirical data whereby both positive and appropriately qualified negative findings are informative.
The studies that comprise the Psychiatric GWAS Consortium (PGC; http://pgc.unc.edu) are shown in Table 1. GWAS data for ADHD, autism, bipolar disorder, major depressive disorder and schizophrenia from 42 samples of European subjects should be available for mega-analyses by early 2009 (>59 000 independent cases and controls and >7700 family trios). To our knowledge, the PGC will have access to the largest set of GWAS data available.
A major change in human genetics in the past 5 years has been in the growth of controlled-access data repositories, and individual phenotype and genotype data are now available for many of the studies in Table 1. When the PGC mega-analyses are completed, most data will be available to researchers via the NIMH Human Genetics Initiative (http://nimhgenetics.org). Although the ready availability of GWAS data is a benefit to the field by allowing rapid application of a wide range of analytic strategies to GWAS data, there are potential disadvantages. GWAS mega-analysis is complex and requires considerable care and expertise to be done validly. For psychiatric phenotypes, there is the additional challenge of working with disease entities based largely on clinical description, with unknown biological validity and having both substantial clinical variation within diagnostic categories as well as overlaps across categories.13 Given the urgent need to know if there are replicable genotype–phenotype associations, a new type of collaboration was required.
The purpose of the PGC is to conduct rigorous and comprehensive within- and cross-disorder GWAS mega-analyses. The PGC began in early 2007 with the principal investigators of the four GAIN GWAS,14 and within six months had grown to 110 participating scientists from 54 institutions in 11 countries. The PGC has a coordinating committee, five disease-working groups, a cross-disorder group, a statistical analysis and computational group, and a cluster computer for statistical analysis. It is remarkable that almost all investigators approached agreed to participate and that no one has left the PGC. Most effort is donated but we have obtained funding from the NIMH, the Netherlands Scientific Organization, Hersenstichting Nederland and NARSAD.
The PGC has two major specific aims. (1) Within-disorder mega-analyses: conduct separate mega-analyses of all available GWAS data for ADHD, autism, bipolar disorder, major depressive disorder, and schizophrenia to attempt to identify genetic variation convincingly associated with any one of these five disorders. (2) Cross-disorder mega-analyses: the clinically-derived DSM-IV and ICD-10 definitions may not directly reflect the fundamental genetic architecture.15 There are two subaims. (2a) Conduct mega-analysis to identify genetic variation convincingly associated with conventional definitions of two or more disorders. This nosological aim could assist in delineating the boundaries of this set of disorders. (2b) An expert working group will convert epidemiological and genetic epidemiological evidence into explicit hypotheses about overlap among these disorders, and then conduct mega-analyses based on these definitions (for example, to examine the lifetime presence of idiopathic psychotic features without regard to diagnostic context).
The goal of the PGC is to identify convincing genetic variation-disease associations. A convincing association would be extremely unlikely to result from chance, show consistent effect sizes across all or almost all samples and be impervious to vigorous attempts to disprove the finding (for example, by investigating sources of bias, confirmatory genotyping, and so on). Careful attention will be paid to the impact of potential sources of heterogeneity17 with the goal of assessing its impact without minimizing its presence.
Biological plausibility is not an initial requirement for a convincing statistical association, as there are many examples in human genetics of previously unsuspected candidate genes nonetheless showing highly compelling associations. For example, multiple SNPs in intron 1 of the FTO gene were associated with body mass index in 13 cohorts with 38 759 participants18 and yet ‘FTO’ does not appear in an exhaustive 116 page compilation of genetic studies of obesity.19 Some strong associations are in gene deserts: multiple studies have found convincing association between prostate cancer and a region on 8q24 that is ~250 kb from the nearest annotated gene.20 Both of these examples are being intensively investigated and we suspect that a compelling mechanistic ‘story’ will emerge in the near future. The presence of a compelling association without an obvious biological mechanism establishes a priority research area for molecular biology and neuroscience of a psychiatric disorder.
The PGC will use mega-analysis as the main analytic tool as individual-level data will be available from almost all samples. To wield this tool appropriately, a number of preconditions must be met. First, genotype data from different GWAS platforms must be made comparable as the direct overlap between platforms is often modest. This requires meticulous quality control for the inclusion of both SNPs and subjects and attention to the factors that can cause bias (for example, population stratification, cryptic relatedness or genotyping batch effects). Genotype harmonization can be accomplished using imputation (21, 22, for example) so that the same set of ~2 million23, 24 directly or imputed SNP genotypes are available for all subjects. Second, phenotypes need to be harmonized across studies. This is one of the most crucial components of the PGC and we are fortunate to have world experts directing the work. Third, the mega-analyses will assess potential heterogeneity of associations across samples.
A decision-tree schematic of the potential outcomes of the PGC mega-analyses is shown in Figure 1. Note that many of the possibilities in Figure 1 are not mutually exclusive and different disorders may take different paths through this framework. It is possible that there eventually will be dozens or hundreds of sequence variants strictly associated with these disorders with frequencies ranging from very rare to common.
………
GWAS has the potential to yield considerable insights but it is no panacea and may well perform differently for psychiatric disorders. Even if these psychiatric GWAS efforts are successful, the outcomes will be complex. GWAS may help us learn that clinical syndromes are actually many different things—for example, proportions of individuals with schizophrenia might evidence associations with rare CNVs of major effect,5, 6 with more common genetic variation in dozens (perhaps hundreds) of genomic regions, between genetic variation strongly modified by environmental risk factors, and some proportion may be genetically indistinguishable from the general population. Moreover, as fuel to long-standing ‘lumper versus splitter’ debates in psychiatric nosology, empirical data might show that some clinical disorders or identifiable subsets of subjects might overlap considerably.
The critical advantage of GWAS is the search of a ‘closed’ hypothesis space. If the large amount of GWAS data being generated are analyzed within a strict and coherent framework, it should be possible to establish hard facts about the fundamental genetic architecture of a set of important psychiatric disorders—which might include positive evidence of what these disorders are or exclusionary evidence of what they are not. Whatever the results, these historically large efforts should yield hard facts about ADHD, autism, bipolar disorder, major depressive disorder and schizophrenia that may help guide the next era of psychiatric research.
- Pe’er I, Yelensky R, Altshuler D, Daly MJ. Estimation of the multiple testing burden for genomewide association studies of nearly all common variants. Genet Epidemiol 2008; 32: 381–385. | Article | PubMed |
- Weiss LA, Shen Y, Korn JM, Arking DE, Miller DT, Fossdal R et al. Association between microdeletion and microduplication at 16p11.2 and autism. N Engl J Med 2008; 358: 667–675. | Article | PubMed | ChemPort |
Letter
Hreinn Stefansson1,36, et al. Large recurrent microdeletions associated with schizophrenia. Nature 455, 232-236 (11 September 2008) | doi:10.1038/nature07229; Received 17 April 2008; Accepted 8 July 2008; Corrected 11 September 2008
Reduced fecundity, associated with severe mental disorders1, places negative selection pressure on risk alleles and may explain, in part, why common variants have not been found that confer risk of disorders such as autism2, schizophrenia3 and mental retardation4. Thus, rare variants may account for a larger fraction of the overall genetic risk than previously assumed. In contrast to rare single nucleotide mutations, rare copy number variations (CNVs) can be detected using genome-wide single nucleotide polymorphism arrays. This has led to the identification of CNVs associated with mental retardation4, 5 and autism2. In a genome-wide search for CNVs associating with schizophrenia, we used a population-based sample to identify de novoCNVs by analysing 9,878 transmissions from parents to offspring. The 66 de novo CNVs identified were tested for association in a sample of 1,433 schizophrenia cases and 33,250 controls. Three deletions at 1q21.1, 15q11.2 and 15q13.3 showing nominal association with schizophrenia in the first sample (phase I) were followed up in a second sample of 3,285 cases and 7,951 controls (phase II). All three deletions significantly associate with schizophrenia and related psychoses in the combined sample. The identification of these rare, recurrent risk variants, having occurred independently in multiple founders and being subject to negative selection, is important in itself. CNV analysis may also point the way to the identification of additional and more prevalent risk variants in genes and pathways involved in schizophrenia.
The C4 gene can exist in multiple copies (from one to four) on each copy of chromosome 6, and has four different forms: C4A-short, C4B-short, C4A-long, and C4B-long. The researchers first examined the “structural alleles” of the C4 locus—that is, the combinations and copy numbers of the different C4 forms—in healthy individuals. They then examined how these structural alleles related to expression of both C4Aand C4B messenger RNAs (mRNAs) in postmortem brain tissues.
From this the researchers had a clear picture of how the architecture of the C4 locus affected expression ofC4A and C4B. Next, they compared DNA from roughly 30,000 schizophrenia patients with that from 35,000 healthy controls, and a correlation emerged: the alleles most strongly associated with schizophrenia were also those that were associated with the highest C4A expression. Measuring C4A mRNA levels in the brains of 35 schizophrenia patients and 70 controls then revealed that, on average, C4A levels in the patients’ brains were 1.4-fold higher.
C4 is an immune system “complement” factor—a small secreted protein that assists immune cells in the targeting and removal of pathogens. The discovery of C4’s association to schizophrenia, said McCarroll, “would have seemed random and puzzling if it wasn’t for work . . . showing that other complement components regulate brain wiring.” Indeed, complement protein C3 locates at synapses that are going to be eliminated in the brain, explained McCarroll, “and C4 was known to interact with C3 . . . so we thought well, actually, this might make sense.”
McCarroll’s team went on to perform studies in mice that revealed C4 is necessary for C3 to be deposited at synapses. They also showed that the more copies of the C4 gene present in a mouse, the more the animal’s neurons were pruned.
Synaptic pruning is a normal part of development and is thought to reflect the process of learning, where the brain strengthens some connections and eradicates others. Interestingly, the brains of deceased schizophrenia patients exhibit reduced neuron density. The new results, therefore, “make a lot of sense,” said Cardiff University’s Andrew Pocklington who did not participate in the work. They also make sense “in terms of the time period when synaptic pruning is occurring, which sort of overlaps with the period of onset for schizophrenia: around adolescence and early adulthood,” he added.
“[C4] has not been on anybody’s radar for having anything to do with schizophrenia, and now it is and there’s a whole bunch of really neat stuff that could happen,” said Sullivan. For one, he suggested, “this molecule could be something that is amenable to therapeutics.”
UniProtKB
Derived from proteolytic degradation of complement C4, C4a anaphylatoxin is a mediator of local inflammatory process. It induces the contraction of smooth muscle, increases vascular permeability and causes histamine release from mast cells and basophilic leukocytes.
Non-enzymatic component of C3 and C5 convertases and thus essential for the propagation of the classical complement pathway. Covalently binds to immunoglobulins and immune complexes and enhances the solubilization of immune aggregates and the clearance of IC through CR1 on erythrocytes. C4A isotype is responsible for effective binding to form amide bonds with immune aggregates or protein antigens, while C4B isotype catalyzes the transacylation of the thioester carbonyl group to form ester bonds with carbohydrate antigens.
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