MILESTONES IN MEDICAL SCIENCE:

Preventing Brain Cell Death Associated with Parkinson's

March 2015

In a pair of related studies, Scripps Florida scientists led by TSRI professor Philip LoGrasso have shown their drug candidates can target biological pathways involved in the destruction of brain cells in Parkinson's disease.

Phil LoGrasso is a professor at The Scripps Research Institute's Florida campus.

The studies suggest that it is possible to design highly effective and highly selective (targeted) drug candidates that can protect the function of mitochondria, which provide the cell with energy, ultimately preventing brain cell death. The discoveries could also lead to new treatment approaches for Alzheimer's disease and ALS (Lou Gehrig's disease).

The drug candidates act on what are known as the JNK (pronounced “junk”) kinases – JNK1, JNK2, and JNK3 – each an enzyme with a unique biological function. During periods of cellular stress, such as exposure to UV radiation, JNK migrates to the mitochondria. That migration, coupled with JNK activation, is associated with many of the hallmark components of Parkinson's disease, such as oxidative stress and programmed cell death.

“These are the first isoform selective JNK 2/3 inhibitors that can penetrate the brain and the first shown to be active in functional cell-based tests that measure mitochondrial dysfunction,” said Dr. LoGrasso. “In terms of their potential use as therapeutics, they've been optimized in every way but one – their oral bioavailability. That's what we're working on now.”

The new studies raise the hope that such a therapy could prevent the gradual degeneration of brain cells in Parkinson's disease and halt these patients' decline.

“Some of these compounds had a level of selectivity that ranged as high as 20,000-fold against competing targets and were extremely effective against oxidative stress and mitochondrial dysfunction – both potent cell killers,” added HaJeung Park, director of Scripps Florida's X-ray Crystallography Core Facility and the first author of the Scientific Reports study.

The scientists found that within JNK3, a single amino acid – L144 – was primarily responsible for the high level of JNK3 selectivity. Isoform selectivity can help to limit potential side effects of a drug.

Intriguingly, some recent studies have shown that JNK3 not only plays a central role in brain cell death in Parkinson's disease, but also in Alzheimer's disease. Dr. LoGrasso and his colleagues also believe their JNK3 drug candidates have the potential to treat ALS (Lou Gehrig's disease).

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