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Could overlooked unstable Repeat DNA explain the missing heritability of schizophrenia and bipolar disorder? A revised hypothesis points to glutamine
https://www.eurekalert.org/news-releases/1149914
EXCERPTS: Schizophrenia and bipolar disorder run in families with a stubbornness that twin studies put at 81 percent heritability. Yet the vast genetic surveys of recent decades have found only part of that inheritance; common variants explain about a quarter of the risk. In a peer-reviewed Perspective in Genomic Psychiatry, a team from Bharati Vidyapeeth Deemed University in Pune, India, proposes where to look for the rest: short, stuttering stretches of DNA that the standard genome-wide methods largely overlooked.
The stutter in question is CAG, a three-letter genetic code for the amino acid glutamine, repeated again and again. Expanded far enough in a single gene, such repeats cause Huntington disease and several spinocerebellar ataxias, illnesses in which schizophrenia-type and bipolar-type psychosis is reported far more often than in the general population.
Mahabaleshwar V. Hegde, Director of the Centre for Innovation in Nutrition Health and Disease at Interactive Research School for Health Affairs, in University and corresponding author, with Asavari A. Joshi, Yogesh S. Badhe, and Anvita A. Kale, asks a simple question. “What if many modest repeat containing genes, scattered across the brain, could add up to cause highly debilitating chronic mental health condition”.
[...] Mahableshwar Hegde and colleagues suggest that newly identified polymorphic CAG repeat genes initiate upstream events in psychosis and GWAS identified risk genes carry out the rest of the complementary steps that results in positive, negative and cognitive impairment symptoms of schizophrenia and mood swing depression of bipolar disorder.
The proposed chain runs through astrocytes, the support cells that supply neurons with glutamine, the raw material for glutamate and GABA, the main carriers of excitatory and inhibitory signals. If many genes produce proteins with enlarged glutamine stretches, the authors reason, astrocytes face an outsized demand of glutamine.
Where would the extra glutamine come from? Astrocytes, in this model, switch on a metabolic side route to make more alpha-ketoglutarate, scavenge ammonia from sources that include D-serine and glycine (two molecules NMDA receptors need to work), and adenosine and hold glutamine back instead of exporting it to neurons.
Neurons would then run short of glutamate, GABA, and the antioxidant glutathione. Glutamine piling up inside astrocytes could behave like a Trojan horse, a term borrowed from hepatic encephalopathy, where trapped glutamine swells astrocytes and turns them reactive. Reactive astrocytes can release inflammatory signals, recruit complement, and eliminate synapses. Circuits break, and in this model, psychosis follows.
Why would one root produce two different illnesses schizophrenia and bipolar disorder and their subtypes? The authors propose that the answer lies in geography: which brain regions the expanded genes act in, and which receptors those regions carry, with NMDA receptor hypofunction favouring schizophrenia-type symptoms and metabotropic glutamate receptor 5 implicated in bipolar disorder.
[...] “Schizophrenia and bipolar disorder are neurodevelopmental disorders, and in this model the metabolic burden accumulates until it crosses a threshold,” .said Hegde “Because the mechanism we propose involves glutamate deficits rather than excitotoxicity, it does not predict neuronal death, which fits a neurodevelopmental rather than a neurodegenerative course.” (MORE - missing details, no ads)
https://www.eurekalert.org/news-releases/1149914
EXCERPTS: Schizophrenia and bipolar disorder run in families with a stubbornness that twin studies put at 81 percent heritability. Yet the vast genetic surveys of recent decades have found only part of that inheritance; common variants explain about a quarter of the risk. In a peer-reviewed Perspective in Genomic Psychiatry, a team from Bharati Vidyapeeth Deemed University in Pune, India, proposes where to look for the rest: short, stuttering stretches of DNA that the standard genome-wide methods largely overlooked.
The stutter in question is CAG, a three-letter genetic code for the amino acid glutamine, repeated again and again. Expanded far enough in a single gene, such repeats cause Huntington disease and several spinocerebellar ataxias, illnesses in which schizophrenia-type and bipolar-type psychosis is reported far more often than in the general population.
Mahabaleshwar V. Hegde, Director of the Centre for Innovation in Nutrition Health and Disease at Interactive Research School for Health Affairs, in University and corresponding author, with Asavari A. Joshi, Yogesh S. Badhe, and Anvita A. Kale, asks a simple question. “What if many modest repeat containing genes, scattered across the brain, could add up to cause highly debilitating chronic mental health condition”.
[...] Mahableshwar Hegde and colleagues suggest that newly identified polymorphic CAG repeat genes initiate upstream events in psychosis and GWAS identified risk genes carry out the rest of the complementary steps that results in positive, negative and cognitive impairment symptoms of schizophrenia and mood swing depression of bipolar disorder.
The proposed chain runs through astrocytes, the support cells that supply neurons with glutamine, the raw material for glutamate and GABA, the main carriers of excitatory and inhibitory signals. If many genes produce proteins with enlarged glutamine stretches, the authors reason, astrocytes face an outsized demand of glutamine.
Where would the extra glutamine come from? Astrocytes, in this model, switch on a metabolic side route to make more alpha-ketoglutarate, scavenge ammonia from sources that include D-serine and glycine (two molecules NMDA receptors need to work), and adenosine and hold glutamine back instead of exporting it to neurons.
Neurons would then run short of glutamate, GABA, and the antioxidant glutathione. Glutamine piling up inside astrocytes could behave like a Trojan horse, a term borrowed from hepatic encephalopathy, where trapped glutamine swells astrocytes and turns them reactive. Reactive astrocytes can release inflammatory signals, recruit complement, and eliminate synapses. Circuits break, and in this model, psychosis follows.
Why would one root produce two different illnesses schizophrenia and bipolar disorder and their subtypes? The authors propose that the answer lies in geography: which brain regions the expanded genes act in, and which receptors those regions carry, with NMDA receptor hypofunction favouring schizophrenia-type symptoms and metabotropic glutamate receptor 5 implicated in bipolar disorder.
[...] “Schizophrenia and bipolar disorder are neurodevelopmental disorders, and in this model the metabolic burden accumulates until it crosses a threshold,” .said Hegde “Because the mechanism we propose involves glutamate deficits rather than excitotoxicity, it does not predict neuronal death, which fits a neurodevelopmental rather than a neurodegenerative course.” (MORE - missing details, no ads)