Basic dietary enhancement enhances schizophrenic traits in mice

Overview

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• Source: University of Tokyo


• Date: 20 Apr,2021

After additional experiments, including visualizing the fluorescently stained dancing advantage of brain cells, researchers concluded that the nutritional supplement likely protects proteins which build neurons’ mobile skeletons.

The supplement betaine was initially isolated from sugar beets and is often associated with sweetness or umami flavor. Healthy levels of betaine come from both outside food sources and internal synthesis within the body. Betaine supplements are already used clinically to treat the metabolic disorder homocystinuria.

“I don’t encourage anybody to take betaine for no reason, if a doctor has not recommended it. Hirokawa was part of the Japan Academy, a national honorary organization recognizing scientific accomplishment, since 2004 and received a Person of Cultural Merit award from the Japanese government in 2013.

Genetic studies of people diagnosed with schizophrenia have found possible connections between the disease and variations in the kinesin family 3b (kif3b) gene as well as another gene involved in the body’s internal synthesis of betaine.

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.”

Nobutaka Hirokawa, M.D., Ph.D., Project Professor, University of Tokyo Graduate School of Medicine

Hirokawa and his lab members have categorized all 45 members of the kinesin superfamily of genes in mammals, most of which encode motor proteins that move materials throughout the cell. Normally, the KIF3B protein joins together with a different kinesin superfamily protein and transports cargo throughout a neuron by traveling up and down the cell’s skeleton.

Mice used in the recent study had only one functional copy of the kif3b gene and are often used as an animal model of schizophrenia. These mice prevent social interactions and reveal the same weak response as human patients with schizophrenia at a test called prepulse inhibition, which measures how startled they are by a sudden, loud noise preceded by a quieter sound.

Kif3b mutant mice raised on a diet supplemented with three times the normal quantity of betaine had regular behaviour, indicating that betaine supplements could treat schizophrenia symptoms.

To determine why betaine had this effect on mice, researchers grew nerve cells with the kif3b mutation in the lab and added fluorescent labels so that they could watch the cellular skeleton take shape.

The shape of a healthy neuron is reminiscent of a tree: a cell body surrounded by branches, the dendrites, attached to a long trunk, the axon. Kif3b mutant neurons grown in the lab have an unusual, hyperbranched structure with too many dendrites. Similar hyperbranched neurons can also be seen in brain samples donated by people with schizophrenia, no matter what treatments or medications they took while they were alive.

During healthy neuron growth, the main body of the cell fills with a skeleton element called tubulin. Meanwhile, the front growth cone of the cell builds outwards in a spiky, erratic dance due to the motions of another skeleton component called filamentous actin. In kif3b mutants, this dance motion, which experts refer to as lamellipodial dynamics, is noticeably reduced and the division between tubulin and actin is blurred.

The actin in a neuron’s cellular skeleton is constructed in part by another protein called CRMP2. Chemical analyses of the brains of kif3b mutant mice and human schizophrenia patients reveal significant chemical harm to CRMP2, which causes the proteins to clump together.

Betaine is known to prevent the type of chemical damage, carbonyl stress, that causes this CRMP2 dysfunction.

“In postmortem brains of schizophrenia patients, CRMP2 is the protein in the brain with the most carbonyl stress. Betaine probably eliminates the carbonyl stress part of the schizophrenia equation,” said Hirokawa.

By shielding CRMP2 from damage, betaine treatment allows kif3b mutant neurons to build proper structures. With a structurally sound skeleton to browse, the remaining functional KIF3B protein could shuttle freight around the cell. Other test tube experiments revealed that KIF3B and CRMP2 can bind together, but their exact relationship remains unclear.

“We know that the quantity of betaine decreases in schizophrenia patients’ brains, so this study suggests that betaine could be curative for at least some kinds of schizophrenia,” said Hirokawa.

The UTokyo research team is planning future collaborations with pharmaceutical companies and clinical studies of betaine supplements as a treatment for schizophrenia.