Enormous transporter protein dysfunction related with schizophrenia

Overview

• Post By : Kumar Jeetendra


• Source: Kyoto University


• Date: 29 Dec,2020

Researchers have suspected mutations in a cellular cholesterol transport protein are associated with psychiatric disorders, but have found it hard to show this and to pinpoint how it happens. Currently, Kazumitsu Ueda of Kyoto University’s Institute for Integrated Cell-Material Sciences (iCeMS) and colleagues in Japan have provided evidence that mice with disrupted ABCA13 protein demonstrate a hallmark behavior of schizophrenia. The team researched ABCA13’s roles and published their findings in the Journal of Biological Chemistry.

ABCA13 belongs to a family of mobile transporter proteins known as ATP-binding cassette (ABC) proteins, which are involved in transferring cholesterol and other molecules into and out of cells. Ueda and his team have been studying ABC proteins for 35 years, providing them extra leverage for discovering the elusive roles of what is supposed to be the largest of these proteins, ABCA13.

We found that ABCA13 accelerates the internalization of cholesterol in cells and that its loss of function is associated with the pathophysiology of some psychiatric disorders.”

Kazumitsu Ueda, Kyoto University’s Institute for Integrated Cell-Material Sciences

The scientists analyzed ABCA13 in different types of human cells. They also turned off the gene that codes for the protein in mice. Finally, they investigated the effects of mutated ABCA13 proteins in human cells. The team found that ABCA13 was a huge protein localized in cellular vesicles, and helps transport cholesterol from the cell’s membrane to the vesicles.

Ordinarily, a feeble’prepulse’ stimulus, like a sound, can reduce the feeling of being startled by a subsequent stronger stimulation. However, people with some psychiatric disorders, still feel startled by a main stimulus despite being preceded by a prepulse. The scientists found that both normal mice and the mice lacking ABCA13 had a normal startle response. But just the engineered mice were startled when the startling stimulus was preceded by a prepulse.

The scientists further wanted to know how ABCA1 deletion affected nerve cells in the brain. They found that vesicles in brain nerve endings in the mice which lacked ABCA1 did not accumulate cholesterol. Synaptic nerve vesicles are vital for the transmission of information from one nerve to another, so this error could contribute to the pathophysiology of psychiatric disorders, the researchers say.

Finally, the scientists analyzed human cells containing mutated versions of ABCA13 thought to be related to some psychiatric disorders. They found the mutations diminished ABCA13’s functions and capability to locate within cellular vesicles.

The group suggests further studies on ABCA13 functions could lead to the development of novel therapeutic approaches for psychiatric disorders like schizophrenia, bipolar disorder and major depression.