April 15, 2014

From Johns Hopkins: A New Technique to Protect Dopamine-Producing Cells from Deteriorating?

On April 10, the journal Cell reported an interesting development: Researchers at Johns Hopkins identified – and then disabled -- a cellular mechanism in human neurons that triggers a particular type of Parkinson’s disease. The scientists think their discovery could lead to new treatments for people with PD.

The breakthrough was a long time in coming. Building on many years of work to find a biological cause for Parkinson's, the Hopkins scientists hope their new discovery could eventually produce techniques to retard or even prevent the deterioration of dopamine-producing neurons -- the process which leads to PD.

Mutations in the Enzyme LRRK2
About ten years ago, researchers identified a link between Parkinson’s and a mutation in the enzyme "leucine-rich repeat kinase 2" (LRRK2), pronounced “lark2,” which strengthened the notion that PD might have some type of genetic origin. 

At that time, Dr. Ted Dawson (professor of neurology and director of the Johns Hopkins Institute for Cells Engineering) and his wife, Dr. Valina Dawson (professor of neurology and member of the Institute for Cell Engineering) cloned the enzyme, and discovered that it was actually a "kinase" -- a specific type of enzyme that transfers phosphate groups to proteins, and even manipulates the proteins, turning them on and off.

In time, researchers learned they could slow the deterioration of dopamine-producing neurons by obstructing this kinase activity in mutated LRKK2 enzymes. Conversely, they could also speed up the death of those brain cells by activating that kinase process to cell proteins.

But there was a catch: scientists didn’t know specifically which protein(s) LRKK2 was affecting. So – as Dawkins describes it – he “went fishing,” using LRKK2 as his “bait” to identify the protein(s).

Dawkins soon learned that many of the proteins he investigated seemed to play a key role in cellular machinery. Did LRKK2 play some similar role in the manufacture or activity of proteins?

Which Protein(s) Did the LRRK2 Enzyme Affect?
To find out, Dawkins tested the proteins he identified to see if any of them might accept phosphate groups from LRRK2, the same transfer process he and his wife had associated with LRRK2 years before. It gets a little technical, but here goes: The team identified three protein candidates. Then they began altering the proteins to see what might happen. 

In the process, they discovered that creating a mutation in protein “s15” (which blocked LRRK2’s ability to transfer phosphate groups) somehow protected nerve cells from deteriorating in humans, rats, and fruit flies.

In short, the scientists – knowing a link existed between PD and the mutated LRRK2 enzyme, and knowing how that mutation promoted the development and progress of PD  -- discovered the target protein that allowed them to disable the particular cellular mechanism that led to PD.

Said Dawson, "When you go fishing, you want to catch fish. We just happened to catch a big one.”

The Hopkins team now wants to learn exactly how excess protein production leads to the death of dopamine-producing neurons. They also want to take what they learned from nerve cells in a dish and apply it to studies on mice. If blocking the damaging protein mechanism works to prevent cell death in living rodents, they’ll keep going.

“There's a big chasm between animal disease models and human treatments,” said Dr. Ian Martin, a neuroscientist in Dawson’s lab and the lead author on the paper. “But it’s exciting. I think it definitely could turn into something real, hopefully in my lifetime.”

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For years, the Michael J. Fox Foundation has been supporting research on the LRRK2 enzyme, which it describes as "the greatest known genetic contributor to Parkinson’s disease." Here is the foundation's page, LRRK2 and Parkinson's Disease.

On April 10, 2014, Johns Hopkins issued this press release about Dawson's discovery, titled "Getting To The Root Of Parkinson's Disease."

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