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Tuesday, July 4, 2017

New drug target for Parkinson's disease found

By , July 4, 2017

A new study may have found a target for a potential drug for Parkinson's disease

A new study has found an enzyme that drives neurotoxicity in both Alzheimer's and Parkinson's disease. Blocking the action of this enzyme may prevent these conditions from developing, so the research may have found a new drug target. 

It is currently estimated that more than 5 million people in the United States are living with Alzheimer's disease, and as many as 1 in 3 elders are said to die with the condition, or another form of dementiaParkinson's disease also affects approximately 60,000 U.S. adults every year. 
Both diseases are neurodegenerative, meaning that brain cells progressively and irreversibly degenerate until they eventually die.
Even though there are various differences between the two conditions on a genetic and structural level, a team of scientists at Emory University in Atlanta, GA, may have found an enzyme that triggers both of them. This newly discovered enzyme could be a target for a potential drug for Parkinson's disease. 
The new study was led by Keqiang Ye, Ph.D., and the findings were published in the journal Nature Structural and Molecular Biology.

The tau and alpha-synuclein proteins

One aspect shared by the two conditions regards disease formation: both conditions are characterized by a clumpy protein capable of killing brain cells. This protein is called alpha-synuclein in Parkinson's disease, and tau in Alzheimer's disease. 
In Parkinson's disease, it is believed that alpha-synuclein aggregates and forms clumps called Lewy bodies. These clumps can be found in the outer layer of the cerebrum, as well as deeper inside the midbrain. 
In Alzheimer's disease, an excess production of tau forms tangles that can obstruct the transportation of nutrients to neurons, which die as a result of this starvation.
Previous research carried out by Dr. Ye and colleagues found an enzyme called asparagine endopeptidase (AEP), which makes tau clumpier and more toxic. The new research hypothesized that AEP would have the same enhancing effect on alpha-synuclein.
In Parkinson's, alpha-synuclein behaves much like tau in Alzheimer's. We reasoned that if AEP cuts tau, it's very likely that it will cut alpha-synuclein too." 

Keqiang Ye, Ph.D.
This is a Parkinson’s disease brain sample, stained with an antibody that only recognizes the N103 chunk of alpha-synuclein, which is generated through cleavage by AEP. image is credited to From Zhang et al NSMB (2017).

AEP and neurotoxicity in Parkinson's

As expected, Dr. Ye and team found that AEP drives the aggregation of alpha-synuclein and increases its neurotoxicity. In the mouse model designed by the researchers, AEP-induced neurotoxicity lead to a loss of neurons and motor deficits.
The researchers also found that AEP has a scissor-like, "cleaving" effect on human alpha-synuclein. Cleaved fragments of alpha-synuclein were found to be likelier to form clumps than the full-length form of the protein. When introduced in the cells or brains of mice, the neurotoxicity of the cleaved protein was higher. 
Additionally, the researchers mutated the protein so that AEP could not cleave it, and they found that the uncut protein was less toxic. 
Furthermore, Dr. Ye and colleagues found cleaved fragments of alpha-synuclein in brain tissue samples from people with Parkinson's disease, but not in samples from healthy controls. 
In the healthy control samples, the researchers found AEP exclusively in lysosomes, which are tiny organelles within the cell that act as its "digestive system." But in the tissue samples of people with Parkinson's disease, AEP overflowed into other parts of the cell. 
These findings could point to a new target for a potential anti-Parkinson's drug.  Trials in animal models have already shown that an AEP-inhibiting drug preserves memory and may have a preventive effect against Alzheimer's disease. 
Although the researchers note that AEP is not the only enzyme that breaks down alpha-synuclein, thus making it more toxic, Dr. Ye and team are also planning to test AEP-inhibiting drugs in animals with Parkinson's disease.

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