Team takes a new approach to taming neuroinflammation

Scripps' Benjamin Cravatt

There's an inflammatory lipid molecule in the brain which--in high concentrations--can trigger a rare inherited neurodegenerative disorder. And a team at Scripps says they've been working on identifying enzymes that influence its production, offering a prime target for drug developers and work that could offer some insights that may also assist investigators in much bigger fields involving brain inflammation, such as multiple sclerosis, Alzheimer's, Parkinson's and ALS.

The rare disease is called PHARC, and it was ID'd about 6 years ago by Norwegian investigators. The disease usually starts to spur symptoms during adolescence, worsening progressively with age.

In follow-up work, researchers found that the ABHD12 enzyme is relied on to break down immune-signaling lipid molecules called lysophosphatidylserines (lyso-PSs) in the brain. ABHD12's absence in PHARC mice models leads to an abnormal buildup of lyso-PSs and subsequent neuroinflammation, they concluded. So finding drugs that build lyso-PSs would restore the natural balance and reduce inflammation.

The team was able to link the lyso-PS-making activity in mouse brains specifically to a previously uncharacterized enzyme called ABHD16A.

In further work, Cravatt's team began a collaboration with the laboratory of chemist Amy Howell at the University of Connecticut to find the ideal inhibitor of ABHD16A, initially as a tool for studying the enzyme.

"This finding is a good example of what can be gained from studying enzymes linked to rare human genetic disorders," said Benjamin Cravatt, chair of TSRI's Department of Chemical Physiology and a member of TSRI's Skaggs Institute for Chemical Biology.

- here's the release