HONG KONG — Defects in fatty acid-binding proteins (FABPs) may help to explain the pathology in some cases of schizophrenia and autism spectrum disorders (ASDs), possibly leading to the development of tailor-made therapies for those mental disorders, Japanese neuroscientists reported.

The team of neuroscientists, led by Takeo Yoshikawa, head of the Laboratory for Molecular Psychiatry at the Riken Brain Science Institute in Saitama, Japan, reported those findings in an open access article published in the July 15, 2014, online issue of Human Molecular Genetics.

After identifying genetic mutations in FABP genes in samples taken from patients with schizophrenia and ASD, the researchers demonstrated that genetic disruption of FABP genes in mice mimics certain disease behaviors seen in those patients, suggesting that disruption of FABPs could be a common link underlying some forms of those two prevalent mental disorders.

"We sequenced the exons of genes using DNA samples from 2,170 controls [and those] from 2,097 patients with schizophrenia and 316 patients with autism," Yoshikawa told BioWorld Today.

The study found that FABPs, which play a central role in lipid metabolism, are genetically linked to schizophrenia and ASD in humans and dysfunctional behaviors observed in mice, with those findings providing support for the involvement of lipid metabolism in the spectrum of cognitive disorders.

Lipids are known to perform important structural and signaling functions within the human brain, while disruption of lipid transport to or within the brain itself can lead to anomalous neurological symptoms.

For example, the marked but partially unexplained rise in incidence of ASD seen in recent decades seems to parallel changes in the dietary composition of essential fatty acids, in particular the replacement of cholesterol by omega-6 fatty acids in many food products.

Previous studies at different laboratories also have identified abnormally low levels of some polyunsaturated fatty acids (PUFAs), including essential fatty acids, in schizophrenic and autistic patients, but have failed to identify the proteins responsible for those lipid abnormalities.

In a 2007 study published in PLoS Biology, "we succeeded in identifying FABP7, but two more FABP genes, FABP3 and FABP5, are also abundantly expressed in the brain," Yoshikawa said. "Therefore, in the current work, we have analyzed the three genes using a larger cohort, including samples from autism [patients], and using a more integrative approach."

Yoshikawa and his team investigated the FABPs that facilitate the transport of PUFAs and other fatty acids. "Our prior study showed that disruption of FABP7 in mice impaired neurogenesis, so we suspected that FABP7 and its family members had important roles in neurodevelopment," he said.

The researchers focused on the major FABPs found in mature neurons and neuronal progenitors, including FABP3, FABP5 and FABP7, in order to better understand the potential roles of those protein molecules in mental disabilities, and they found that FABP levels expressed in the postmortem brains and blood cells of patients were altered.

Moreover, they identified specific rare polymorphisms in brain-expressed FABP genes exclusively in schizophrenia and ASD patients, which caused an abnormal structure or function of those proteins, presumably preventing them from delivering the correct fatty acids to target tissues and cell organelles.

To investigate the effect of FABP loss in the brain, the researchers knocked out the genes in mice and conducted a variety of laboratory behavioral tests. They found that mice lacking FABPs exhibited characteristic behaviors similar to those observed in human patients.

For example, FABP3 knockout mice showed decreased memory and social motivation in a range of validated laboratory tests, mirroring the dysfunctional cognition and lack of interest in social communication that is frequently seen in patients with ASD.

In contrast, laboratory testing demonstrated that FABP7 knockout mice displayed hyperactivity and anxiety, a behavioral phenotype that is similar to behaviors observed in patients with schizophrenia.

"Although the amino acid sequence of the FABPs is similar, we think that they interact with different fatty acids and are expressed in different cells with distinct timing during development," Yoshikawa said, adding "this is likely the reason that the behaviors in the mice are different for each member of the FABP family."

PERSONALIZING TREATMENT?

Both schizophrenia and ASD are caused by multiple factors and conventional treatment does not necessarily work well on all patients.

The present findings suggest that FABPs may explain one mechanism for those disorders selectively affecting lipid transport systems that may complement other etiological factors. "Identification of FABP gene mutations in humans may help us take a personalized treatment approach," Yoshikawa said.

"We hope our findings will lead to the development of tailor-made therapies, providing patients with molecules that complement deficiencies caused by their particular [genetic] mutation," he said.

"Fatty acids are now being tested for the prevention of the overt manifestation of schizophrenia, but [it appears] there are both responders and nonresponders. This might be due to the expression levels of FABPs and or the genotypes of FABPs," Yoshikawa added.

"When this issue is resolved, then we could administer more effective personalized medicine, by examining the expression levels of FABPs and or the genotypes of FABPs of the target subjects beforehand," he said.

"If we could identify high-affinity endogenous ligands for FABPs that are as yet unknown, then those compounds are expected to be clinically useful, either as therapeutics or as supplementary treatments."