A study has found that a simple dietary supplement reduces behavioral symptoms in mice with a genetic mutation that causes schizophrenia.
Schizophrenia is estimated to affect about 1 in 100 people globally and is one of the top 15 leading causes of disability worldwide.
The study examined the role of betaine in schizophrenia, as it is known to be reduced in the brains of schizophrenia patients. Betaine, often associated with sweetness or umami flavours, was first isolated from sugar beets and is acquired through the diet and also produced in the body. Betaine supplements are already used clinically to treat the metabolic disease homocystinuria.
“I don’t encourage anyone to take betaine for no reason, if a doctor has not recommended it. But, we know this drug is already used clinically, so repurposing it to treat schizophrenia should be safe,” said study leader Professor Nobutaka Hirokawa, MD, PhD, from the University of Tokyo Graduate School of Medicine.
“There are treatments for schizophrenia, but they have side effects and unfortunately there is still no effective drug for patients to take that we can explain biochemically why it works,” Prof Hirokawa added.
Genetic studies have found possible links between schizophrenia and variations in the kinesin family 3b (kif3b) gene as well as another gene involved in the body’s production of betaine. The researchers categorised all 45 members of the kinesin superfamily of genes in mammals, most of which encode motor proteins that move materials throughout the cell. Together with another protein kinesin superfamily, the KIF3B protein transports cargo throughout a neuron, travelling up and down the cell’s skeleton.
The researchers mice used to model schizophrenia which had only one functional copy of the kif3b gene. These mice have different behaviours to normal mice such as avoiding social interactions and being less startled by a sound test. The Kif3b mutant mice that were raised on a diet with triple the normal amount of betaine had normal behaviour.
To work out why betaine had this effect on mice, researchers grew nerve cells with the kif3b mutation in the laboratory and added fluorescent labels so they could watch the development of cellular skeleton.
Kif3b mutant neurons grown in the lab have an unusual, overly branched structure with too many dendrites, unlike the normal tree-like shape of healthy neurons. Similar overly branched neurons are also seen in brain samples donated by people with schizophrenia, regardless of any treatments or medications they took while alive.
During healthy neuron development, the cell’s main body fills with a skeleton component called tubulin. Meanwhile, the cell’s front growth cone builds outwards in a spiky, erratic dance due to the movements of another skeleton component known as filamentous actin. In kif3b mutants, this dancing movement, which experts refer to as lamellipodial dynamics, is reduced and the distinction between tubulin and actin is blurred.
Chemical analyses of the brains of kif3b mutant mice and human schizophrenia patients reveal significant chemical damage to CRMP2, a protein which helps assemble actin. This damage causes the proteins to clump together. However, betaine is known to prevent the kind of chemical damage, carbonyl stress, responsible for CRMP2 dysfunction.
“In postmortem brains of schizophrenia patients, CRMP2 is the protein in the brain with the most carbonyl stress. Betaine likely eliminates the carbonyl stress portion of the schizophrenia equation,” said Hirokawa.
It appears that by shielding CRMP2 from damage, betaine treatment allows kif3b mutant neurons to build normal structures, allowing the remaining functional KIF3B protein can shuttle cargo around the cell. Other in vitro experiments showed that KIF3B and CRMP2 can bind together, but their exact relationship remains unclear.
“We know that the amount of betaine decreases in schizophrenia patients’ brains, so this study strongly suggests betaine could be therapeutic for at least some kinds of schizophrenia,” said Hirokawa.
Source: Medical Xpress
Journal information: Shogo Yoshihara et al. Betaine ameliorates schizophrenic traits by functionally compensating for KIF3-based CRMP2 transport, Cell Reports (2021). DOI: 10.1016/j.celrep.2021.108971
