Molec­u­lar find could help de­feat Parkin­son’s

The Fresno Bee (Sunday) - - Front Page - BY CATHIE AN­DER­SON can­der­[email protected]

Re­searchers long ago iden­ti­fied a mol­e­cule that they felt held the se­crets to a treat­ment for Parkin­son’s dis­ease, but the tiny pro­tein known as Nurr1 had a com­plex lock that no one has been able to crack for more than a decade.

On Thurs­day, a team at the Univer­sity of Cal­i­for­nia, San Fran­cisco, re­ported that they have pho­to­graphs that show a way in­side Nurr1 and a place where drug­mak­ers could launch an as­sault on Parkin­son’s. Their re­search is on­go­ing, but the lat­est find­ings ap­peared in Cell Chem­i­cal Bi­ol­ogy.

“This mol­e­cule is widely re­garded as an out­stand­ing tar­get for de­vel­op­ing ther­a­peu­tics to treat Parkin­son’s dis­ease,” said Pamela Eng­land, an as­so­ciate pro­fes­sor of phar­ma­ceu­ti­cal chem­istry in UCSF’s School of Phar­macy. “It’s a lot of years that peo­ple have wanted to pur­sue this tar­get and haven’t had the struc­ture, atomic res­o­lu­tion struc­ture...to help them do it.”

Parkin­son’s dis­ease, like Alzheimer’s, ALS and Hunt­ing­ton’s dis­ease, is a pro­gres­sively de­bil­i­tat­ing ill­ness with no cure. Peo­ple who have the con­di­tion find it dif­fi­cult to con­trol moods and mus­cles be­cause neu­rons in the mid­brain can’t ac­cess enough of a key chem­i­cal known as dopamine that trans­mits sig­nals be­tween brain cells.

No one knows why this phe­nom­e­non oc­curs, but it af­fects 10 mil­lion peo­ple around the world.

Ex­ist­ing drugs pro­vide only a tem­po­rary boost to dopamine sig­nal­ing, but UCSF re­searchers said they be­lieve they’ve iden­ti­fied a key­hole on Nurr1. That key­hole, they said in their pa­per, is lo­cated where an­other atom binds to a pocket on Nurr1. To find that pocket, re­searchers at UCSF had to fig­ure out how to crys­tal­lize the Nurr1 mol­e­cule, lo­cate atoms at­tached to it and cre­ate a high-res­o­lu­tion pic­ture of a site where an­other atom had at­tached it­self.

That work be­gan in 2015, and af­ter 18 months, re­searchers

had enough in­for­ma­tion to start test­ing out their hy­pothe­ses and writ­ing the pa­per on their dis­cov­er­ies. Eng­land said that her team found that the mol­e­cule that binds in this pocket is too un­sta­ble and re­ac­tive to be of much use in the ther­a­peu­tic process but that drug­mak­ers will likely try to de­velop other com­pounds that will bind to the site.

Eng­land said the mol­e­cule pho­tographed on Nurr1 is a sub­stance pro­duced when cells dis­pose of ex­cess dopamine. She and other re­searchers did fur­ther ex­per­i­ment on the sub­stance, known as DHI, in lab­o­ra­to­ries and on ze­brafish. They found that it in­creased Nurr1 ac­tiv­ity, stim­u­lat­ing the genes in­volved in stor­ing and pro­duc­ing dopamine.

That is ex­actly what phar­ma­col­o­gists have hoped to achieve with a Nurr1-tar­get­ing drug, Eng­land said.

“We hope these in­sights will lead to drugs that for the first time can tar­get the un­der­ly­ing causes of Parkin­son’s dis­ease,” Eng­land said. “But more im­me­di­ately, this dis­cov­ery will al­low us to bet­ter un­der­stand Nurr1’s role in the ear­li­est stages of the dis­ease. As al­ways, with un­der­stand­ing comes hope.”

It typ­i­cally takes 10 to 15 years to de­velop new drug ther­a­pies, Eng­land said, but the U.S. Food and Drug Ad­min­is­tra­tion could choose to fast-track ther­a­pies that drug­mak­ers can show would not cause harm in tri­als.

“If you’re not go­ing to do any harm, is there a chance you’re go­ing to do some good?” Eng­land asked. “It all de­pends on the dis­ease and how many peo­ple are im­pacted.”

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