New Research Reveals the Mutation of Cholesterol Transporter ABCA13 Associated with Schizophrenia

Scientists have long suspected that the mutation of cholesterol transporter ABCA13 in cells is related to mental illness, but it is difficult to prove this, and it is difficult to determine how it occurs. Now, in a new study, researchers from Kyoto University and other research institutions in Japan have provided evidence that mice with ABCA13 protein damage exhibit characteristic behavior of schizophrenia. They studied the function of ABCA13 and published their research results in the Journal of biological chemistry with the title of “ABCA13 dysfunction associated with psychic disorders causes affected cholesterol traffic”. The corresponding author is Kazumitsu Ueda of the Institute of cell materials science, Kyoto University.

 

ABCA13 belongs to a family of cell transporters called ATP binding cassette (ABC) proteins, which are involved in the migration of cholesterol and other molecules into and out of cells. Ueda and his team have been studying the ABC protein for 35 years, which gives them an additional advantage in discovering the mysterious role of ABCA13, which is suspected to be the largest member of the protein family.

 

 

Ueda’s team studied ABCA13 in different types of human cells. They also turned off the gene that encodes the protein in mice. Finally, they studied the effect of mutated ABCA13 protein in human cells. They found that ABCA13 is a large protein located in cell vesicles that helps transport cholesterol from the cell membrane to these vesicles.

 

“We found that ABCA13 accelerates the internalization of cholesterol in cells, and the loss of its function is related to the pathophysiology of some mental diseases,” Ueda said.

 

Mice lacking ABCA13 look normal and have a normal life span. However, a series of behavioral investigations showed that the results of the start response and prepulse inhibition tests were abnormal. Under normal circumstances, weak prepulse stimulation, such as sound, can reduce the sense of being frightened by subsequent strong stimulation. However, some patients with mental illness will still feel frightened even if they experience a pre-pulse before the main stimulus. They found that normal mice and mice lacking ABCA13 had normal startle responses. However, only mice lacking ABCA13 were frightened when they had a prepulse before the shock stimulus.

 

Ueda’s team further wanted to know how ABCA13 deficiency affects nerve cells in the brain. They found that vesicles in nerve endings did not accumulate cholesterol in ABCA13 deficient mice. They say synaptic nerve vesicles are crucial for the transmission of information in different nerves, so this dysfunction may lead to the pathophysiology of mental illness.

 

Finally, Ueda’s team looked at human cells containing mutant versions of ABCA13 that are thought to be associated with some mental disorders. They found that these mutations impaired the function of ABCA13 and its ability to localize in vesicles.

 

The Ueda team pointed out that further research on the function of ABCA13 may help people develop new treatment strategies for mental diseases such as schizophrenia, bipolar disorder, and major depression.

 

 

Reference

  1. Mitsuhiro Nakato et al. ABCA13 dysfunction associated with psychiatric disorders causes impaired cholesterol trafficking. Journal of Biological Chemistry, 2020, doi:10.1074/jbc.RA120.015997.