A recent study from Johns Hopkins Medicine reveals that both the liver and brain contribute pathways to differing symptoms of the same rare inherited disorder.
Published in the journal Science Advances, the federally funded study used mice genetically engineered to model pyridoxine-dependent epilepsy, a rare disorder caused by mutations in the ALDH7A1 gene. The researchers found that loss of ALDH7A1 in liver cells was primarily responsible for the mice's increased susceptibility to seizures. In contrast, loss of the gene in specialized brain cells called astrocytes was responsible for changes associated with psychiatric symptoms, including depressive-like behavior, reduced motivation, passive coping and decreased self-care. This research adds to growing evidence that neurological and psychiatric symptoms arising from the same genetic mutation can stem from distinct biological and metabolic processes.
The study also found that sulforaphane, an antioxidant compound found in broccoli sprouts, reversed psychiatric symptoms in the mice. While vitamin B6 is used to control seizures in people with pyridoxine-dependent epilepsy, sulforaphane could potentially be added to treatment to address the psychiatric symptoms associated with the disorder.
"An important implication of this work is that the symptoms we see in a rare neurological disorder do not necessarily have to come from the same place or through the same mechanism," says Akira Sawa, M.D., director of the Johns Hopkins Schizophrenia Center and professor of psychiatry and behavioral sciences at Johns Hopkins Medicine. "In this case, we found that the liver and brain each make distinct contributions to the disease, which gives us a much clearer picture of how these symptoms arise."
Pyridoxine-dependent epilepsy, or PDE, is caused by loss-of-function mutations in ALDH7A1. People with the disorder experience severe seizures, which can be ameliorated by high doses of pyridoxine, also known as vitamin B6. However, psychiatric and cognitive symptoms can persist even after seizures are controlled. To investigate whether those symptoms arise through a different mechanism, researchers engineered mice in which ALDH7A1 could be selectively removed from either the liver or astrocytes, star-shaped brain cells that help maintain the environment surrounding neurons.
Mice lacking ALDH7A1 in the liver became more susceptible to seizures but did not develop changes in mood and behaviors seen in mice lacking the gene throughout the body. In contrast, mice lacking the gene specifically in astrocytes developed behavioral deficits without becoming more susceptible to seizures.
The researchers then found that loss of ALDH7A1 in astrocytes disrupted the normal antioxidant defenses that help cells manage reactive molecules and maintain normal function. This disruption was associated with reduced activity among neurons in the prelimbic cortex, a brain region involved in regulating emotional behavior.
Because antioxidant defenses can help maintain this balance, the researchers tested sulforaphane, a compound known to activate NRF2, a cellular pathway that helps protect cells from oxidative stress. They incorporated sulforaphane into the mice's diet and found that it increased NRF2 levels in ALDH7A1-deficient astrocytes, suggesting increased antioxidant protection and improved redox balance.
By contrast, sulforaphane did not correct the increased seizure susceptibility associated with loss of ALDH7A1 throughout the body. That distinction, the researchers say, provided additional evidence that the psychiatric and seizure symptoms are driven by separate mechanisms, with the psychiatric changes linked to astrocytes in the brain and seizure susceptibility linked to dysfunction involving the liver.
"The fact that sulforaphane could improve the psychiatric phenotype while not preventing seizures was especially informative," says Sawa. "It suggests that targeting the biology of the brain directly may be able to address psychiatric symptoms that persist even when the seizures themselves are controlled."
The researchers say the findings provide a foundation for further study of sulforaphane as a potential supplemental treatment for psychiatric symptoms associated with pyridoxine-dependent epilepsy. Future research will be needed to determine whether targeting astrocyte redox imbalance can improve these symptoms in people with the disorder, with mechanism-driven clinical trials of sulforaphane representing a potential next step.
The study was funded by the National Institute of Mental Health and the National Institute on Drug Abuse. Researchers from the Johns Hopkins University School of Medicine departments of neuroscience, psychiatry and behavioral sciences, physiology, pharmacology and therapeutics, biomedical engineering and genetic medicine led the study, with collaborators from the National Institute on Drug Abuse Intramural Research Program, Heidelberg University and the University of Maine.
