We use cookies to understand how you use our site and to improve your experience. This includes personalizing content and advertising. To learn more, click here. By continuing to use our site, you accept our use of cookies. Cookie Policy.

Features Partner Sites Information LinkXpress
Sign In
Advertise with Us
INTEGRA BIOSCIENCES AG

Download Mobile App




Possible New Target Found for Treating Brain Inflammation

By LabMedica International staff writers
Posted on 28 Jan 2015
Print article
Scientists have identified an enzyme that produces a class of inflammatory lipid molecules in the brain. Abnormally high levels of these molecules appear to cause a rare inherited eurodegenerative disorder, and that disorder now may be treatable if researchers can develop suitable drug candidates that suppress this enzyme.

This treatment approach may also become useful against more common disorders that involve brain inflammation—a classification that includes Alzheimer’s, multiple sclerosis, Parkinson’s, amyotrophic lateral sclerosis (ALS), and secondary injury after stroke and head injuries. Such inflammation frequently fails to respond to standard anti-inflammatory drugs. “This finding is a good example of what can be gained from studying enzymes linked to rare human genetic disorders,” said Benjamin F. Cravatt, chair of the department of chemical physiology and member at The Scripps Research Institute’s (TSRI; LA Jolla, CA, USA) Skaggs Institute for Chemical Biology.

The new study by Dr. Cravatt’s team, which was published January 12, 2015, in the journal Nature Chemical Biology, arose from investigations of PHARC, a rare and enigmatic inherited disorder that was first described by Norwegian researchers in 2009. Named for its unique set of typical symptoms (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract) PHARC typically presents in early adolescence and progressively worsens with age.

In 2010, PHARC was associated with gene mutations that inactivate the enzyme ABHD12. The finding encouraged Dr. Cravatt and his colleagues to develop a mouse model of the disease in which the ABHD12 gene is similarly turned off. Studies of those “PHARC mice” revealed that the ABHD12 enzyme typically degrades immune-signaling lipid molecules called lysophosphatidylserines (lyso-PSs) in the brain. ABHD12’s absence in the PHARC mice leads to an abnormal accumulation of lyso-PSs and subsequent neuroinflammation.

Having identified an enzyme that normally breaks down lyso-PS molecules, Dr. Cravatt and his laboratory set out, in the new study, to find an enzyme that makes lyso-PSs. In principle, such an enzyme could be targeted with compounds that inhibit its activity, to tamp down lyso-PS levels in the nervous system and thereby treat PHARC. To find a lyso-PS-making enzyme, Cravatt lab research associate Siddhesh S. Kamat led the effort to develop a sophisticated test for detecting the enzyme-mediated conversion of precursor phosphatidylserine (PS) molecules to lyso-PSs. “Using this test we discovered a cryptic yet distinct lyso-PS-making enzyme activity in the mouse brain,” said Dr. Kamat.

The tests revealed particularly high levels of this activity in the cerebellum, a brain area strongly impacted in PHARC. Moreover, the researchers revealed that this lyso-PS-making activity could be powerfully blocked in the lab dish by the weight-loss drug tetrahydrolipstatin (THL, also known as Orlistat and Xenical). THL is a known inhibitor of multiple enzymes, and the researchers were able to link the lyso-PS-making activity in mouse brain specifically to one of these enzymes: an earlier uncharacterized enzyme called ABHD16A.

In further research, Dr. Cravatt’s team began a collaboration with the laboratory of chemist Amy R. Howell at the University of Connecticut to find a more potent and selective inhibitor of ABHD16A, first as an approach for studying the enzyme. “Dr. Howell very generously allowed us to screen her library of THL-related compounds for ABHD16A inhibitors,” Dr. Cravatt said.

The scientists eventually isolated a small-molecule compound, KC01, which disrupts ABHD16A activity in mammalian cells more selectively than THL does. “Using this inhibitor with advanced chemical proteomic and metabolomics techniques, we were able to confirm that ABHD16A is a major producer of lyso-PS molecules in several different mammalian cells,” Dr. Kamat said.

The scientists found that blocking ABHD16A activity with KC01 markedly reduced secreted lyso-PS levels in culture and brought raised lyso-PS levels back down almost to normal in cells derived from PHARC patients. The treatment also greatly reduced the secretion of inflammatory compounds by PHARC-mouse immune cells (macrophages) following exposure to a bacterial toxin. Finally, the scientists validated the role of ABHD16A by breeding a line of mice whose ABHD16A gene was inactivated. The ABHD16A-knockout animals grew up with lower than usual brain levels of lyso-PSs, and their macrophages showed a correspondingly muted response to immune stimulation.

Dr. Cravatt reported that he hopes to conduct future research in collaboration with the Howell laboratory to develop a better ABHD16A inhibitor that, dissimilar to THL and KC01, can reach the brain from the bloodstream and thus can be tested in live mice—and possibly in PHARC patients someday. “We also think there is a potential for applying the lyso-PS-lowering strategy more broadly against neurological and immunological disorders,” concluded Dr. Cravatt.

Related Links:

The Scripps Research Institute


Platinum Member
COVID-19 Rapid Test
OSOM COVID-19 Antigen Rapid Test
One Step HbA1c Measuring System
GREENCARE A1c
Anti-Cyclic Citrullinated Peptide Test
GPP-100 Anti-CCP Kit
Gold Member
ADAMTS-13 Protease Activity Test
ATS-13 Activity Assay

Print article

Channels

Clinical Chemistry

view channel
Image: Reaching speeds up to 6,000 RPM, this centrifuge forms the basis for a new type of inexpensive, POC biomedical test (Photo courtesy of Duke University)

POC Biomedical Test Spins Water Droplet Using Sound Waves for Cancer Detection

Exosomes, tiny cellular bioparticles carrying a specific set of proteins, lipids, and genetic materials, play a crucial role in cell communication and hold promise for non-invasive diagnostics.... Read more

Molecular Diagnostics

view channel
Image: The study showed the blood-based cancer screening test detects 83% of people with colorectal cancer with specificity of 90% (Photo courtesy of Guardant Health)

Blood Test Shows 83% Accuracy for Detecting Colorectal Cancer

Colorectal cancer is the second biggest cause of cancer deaths among adults in the U.S., with forecasts suggesting 53,010 people might die from it in 2024. While fewer older adults are dying from this... Read more

Hematology

view channel
Image: The Gazelle Hb Variant Test (Photo courtesy of Hemex Health)

First Affordable and Rapid Test for Beta Thalassemia Demonstrates 99% Diagnostic Accuracy

Hemoglobin disorders rank as some of the most prevalent monogenic diseases globally. Among various hemoglobin disorders, beta thalassemia, a hereditary blood disorder, affects about 1.5% of the world's... Read more

Microbiology

view channel
Image: The new platform is designed to perform blood-based diagnoses of nontuberculosis mycobacteria (Photo courtesy of 123RF)

New Blood Test Cuts Diagnosis Time for Nontuberculous Mycobacteria Infections from Months to Hours

Breathing in nontuberculous mycobacteria (NTM) is a common experience for many people. These bacteria are present in water systems, soil, and dust all over the world and usually don't cause any problems.... Read more

Industry

view channel
Image: These new assays are being developed for use on the recently introduced DxI 9000 Immunoassay Analyzer (Photo courtesy of Beckman Coulter)

Beckman Coulter and Fujirebio Expand Partnership on Neurodegenerative Disease Diagnostics

Beckman Coulter Diagnostics (Brea, CA, USA) and Fujirebio Diagnostics (Tokyo, Japan) have expanded their partnership focused on the development, manufacturing and clinical adoption of neurodegenerative... Read more
Copyright © 2000-2024 Globetech Media. All rights reserved.