A team led by scientists at The Scripps Research Institute (TSRI) has 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 neurodegenerative disorder, and that disorder now may be treatable if researchers can develop suitable drug candidates that inhibit this enzyme.
This treatment approach may also turn out to be useful against more common conditions that involve brain inflammation -- a category that includes multiple sclerosis, Alzheimer's, Parkinson's, ALS and secondary damage after stroke and head injuries. Such inflammation often 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 TSRI's Department of Chemical Physiology and member of TSRI's Skaggs Institute for Chemical Biology.
Rare and Mysterious Disorder
The new study by Cravatt's team, which appears as a Nature Chemical Biology Advance Online Publication on January 12, stemmed from investigations of PHARC, a rare and mysterious 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 usually manifests in early adolescence and progressively worsens with age.
In 2010, PHARC was linked to gene mutations that inactivate the enzyme ABHD12. The finding prompted Cravatt and his laboratory to develop a mouse model of the disease in which the ABHD12 gene is similarly inactivated. Studies of those "PHARC mice" revealed that the ABHD12 enzyme normally breaks down immune-signaling lipid molecules called lysophosphatidylserines (lyso-PSs) in the brain. ABHD12's absence in the PHARC mice leads to an abnormal buildup of lyso-PSs and subsequent neuroinflammation.
Having identified an enzyme that normally breaks down lyso-PS molecules, 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 dial down lyso-PS levels in the nervous system and thus treat PHARC.
Sophisticated Test and a Weight-Loss Drug
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 Kamat.
The tests revealed especially high levels of this activity in the cerebellum, a brain region strongly impacted in PHARC.
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Possible new target for treating brain inflammation found