Compound Identified That Alleviates Parkinson’s Symptoms in Mice

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Researchers from Johns Hopkins and the National Cancer Institute (NCI) highlighted

a novel mechanism underlying Parkinson’s disease while simultaneously putting to

rest a previously held theory regarding progression of the disorder. They also

identified a compound that alleviates the disease’s symptoms in mice.

 

The investigators describe their work in a paper titled “Parthanatos mediates

AIMP2-activated age-dependent dopaminergic neuronal loss,” published online in

Nature Neuroscience.

 

“Not only were we able to identify the mechanism that could cause progressive cell

death in both inherited and noninherited forms of Parkinson’s, we found there were

already compounds in existence that can cross into the brain and block this from

happening,” said Valina Dawson, Ph.D., director of the stem cell biology and neuro-

regeneration programs at the Johns Hopkins University School of Medicine’s Institute

for Cell Engineering (ICE). “While there are still many things that need to happen

before we have a drug for clinical trials, we’ve taken some very promising first steps.”

 

Dr. Dawson and her husband, Ted Dawson, M.D., Ph.D., the director of ICE, have

collaborated for decades on studies of the molecular chain of events that lead to

Parkinson’s. One of their findings was that the function of an enzyme called parkin,

which malfunctions in the disease, is to tag a bevy of other proteins for destruction

by the cell’s recycling machinery. This means that nonfunctional parkin leads to the

buildup of its target proteins, and the Dawsons and others are exploring what roles

these proteins might play in the disease.

 

In the new study, the Dawsons collaborated with Debbie Swing and Lino Tessarollo of the

NCI to develop mice whose genes for a protein called AIMP2 could be switched into higher

performance. AIMP2 is one of the proteins normally tagged for destruction by parkin, so

the genetically modified mice enabled the research team to put aside the effects of

defective parkin and excesses of other proteins and look just at the consequences of

too much AIMP2.

 

They found that the mice developed symptoms similar to those of Parkinson’s as they aged.

The brain cells that make dopamine were dying. Since AIMP2 is known for its role in the

process of making new proteins, the researchers thought the cell death was caused by

problems with this process. But when graduate student Yunjong Lee looked at the efficiency

of protein-making in the affected mice, everything appeared normal.

 

Searching for an alternative explanation, Lee tested how cells with excess AIMP2 responded

to compounds blocking various paths to cell death and found that the AIMP2 was activating a

self-destruct pathway called parthanatos, discovered and named by the Dawsons years ago.

 

Lee found that AIMP2 triggered parthanatos by directly interacting with a protein called PARP1,

which was long thought to respond only to DNA damage and not to signals from other proteins.

Dr. Valina Dawson notes that AIMP2 is actually the second protein found to activate PARP1, but

the idea that PARP1 is only involved in detecting and responding to DNA damage is still firmly

entrenched in her field.

 

Since the Dawsons had been studying PARP1 for some time, they knew of compounds drug companies

had designed to block this enzyme. Such drugs are already in the process of being tested to

protect healthy cells during cancer treatment.

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