Large transporter protein linked to schizophrenia

December 29, 2020

Scientists have suspected mutations in a cellular cholesterol transport protein are associated with psychiatric disorders, but have found it difficult to prove this and to pinpoint how it happens. Now, 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 behaviour of schizophrenia. The team investigated ABCA13's functions and published their findings in the Journal of Biological Chemistry.

ABCA13 belongs to a family of cellular transporter proteins called ATP-binding cassette (ABC) proteins, which are involved in moving cholesterol and other molecules into and out of cells. Ueda and his team have been studying ABC proteins for 35 years, giving them extra leverage for uncovering the elusive roles of what is suspected to be the largest of these proteins, ABCA13.

The scientists studied 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 large protein localized in cellular vesicles, and helps transport cholesterol from the cell's membrane into the vesicles.

"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," says Ueda.

Mice lacking ABCA13 looked normal and had a normal lifespan. But a series of behavioural investigations showed abnormal results for the 'startle response and prepulse inhibition test'. Normally, a weak 'prepulse' stimulus, like a sound, can reduce the feeling of being startled by a subsequent stronger stimulus. 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 only 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 that lacked ABCA1 did not accumulate cholesterol. Synaptic nerve vesicles are vital for the transmission of information from one nerve to another, so this malfunction could contribute to the pathophysiology of psychiatric disorders, the researchers say.

Finally, the scientists studied human cells containing mutated versions of ABCA13 thought to be associated with some psychiatric disorders. They found the mutations impaired ABCA13's functions and ability to locate within cellular vesicles.

The team suggests further studies on ABCA13 functions could lead to the development of novel therapeutic strategies for psychiatric disorders like schizophrenia, bipolar disorder and major depression.
-end-
DOI: 10.1074/jbc.RA120.015997

About Kyoto University's Institute for Integrated Cell-Material Sciences (iCeMS):

At iCeMS, our mission is to explore the secrets of life by creating compounds to control cells, and further down the road to create life-inspired materials.
https://www.icems.kyoto-u.ac.jp/

For more information, contact:

I. Mindy Takamiya/Mari Toyama
pe@mail2.adm.kyoto-u.ac.jp

Kyoto University

Related Schizophrenia Articles from Brightsurf:

Schizophrenia: When the thalamus misleads the ear
Scientists at the University of Geneva (UNIGE) and the Synapsy National Centre of Competence in Research (NCCR) have succeeded in linking the onset of auditory hallucinations - one of the most common symptoms of schizophrenia - with the abnormal development of certain substructures of a region deep in the brain called the thalamus.

Unlocking schizophrenia
New research, led by Prof. LIU Bing and Prof. JIANG Tianzi from the Institute of Automation of the Chinese Academy of Sciences and their collaborators have recently developed a novel imaging marker that may help in the personalized medicine of psychiatric disorders.

Researchers discover second type of schizophrenia
In a study of more than 300 patients from three continents, over one third had brains that looked similar to healthy people.

New clues into the genetic origins of schizophrenia
The first genetic analysis of schizophrenia in an ancestral African population, the South African Xhosa, appears in the Jan.

Dietary supplement may help with schizophrenia
A dietary supplement, sarcosine, may help with schizophrenia as part of a holistic approach complementing antipsychotic medication, according to a UCL researcher.

Schizophrenia: Adolescence is the game-changer
Schizophrenia may be related to the deletion syndrome. However, not everyone who has the syndrome necessarily develops psychotic symptoms.

Study suggests overdiagnosis of schizophrenia
In a small study of patients referred to the Johns Hopkins Early Psychosis Intervention Clinic (EPIC), Johns Hopkins Medicine researchers report that about half the people referred to the clinic with a schizophrenia diagnosis didn't actually have schizophrenia.

The ways of wisdom in schizophrenia
Researchers at UC San Diego School of Medicine report that persons with schizophrenia scored lower on a wisdom assessment than non-psychiatric comparison participants, but that there was considerable variability in levels of wisdom, and those with higher scores displayed fewer psychotic symptoms.

Recognizing the uniqueness of different individuals with schizophrenia
Individuals diagnosed with schizophrenia differ greatly from one another. Researchers from Radboud university medical center, along with colleagues from England and Norway, have demonstrated that very few identical brain differences are shared amongst different patients.

Resynchronizing neurons to erase schizophrenia
Today, a decisive step in understanding schizophrenia has been taken.

Read More: Schizophrenia News and Schizophrenia Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.