Enzyme That May Trigger Alpha-Synuclein Aggregates and Parkinson’s Identified by Researchers

An enzyme called asparagine endopeptidase may participate in the development of Parkinson’s disease by cleaving alpha-synuclein protein into toxic fragments, according to new research.

The study, “Asparagine endopeptidase cleaves α-synuclein and mediates pathologic activities in Parkinson’s disease,” was published in the journal Nature Structural and Molecular Biology.

The hallmark of Parkinson’s disease is the formation of alpha-synuclein clumps. But exactly how these clumps form in the brain has not been fully understood.

Now researchers have identified an enzyme called asparagine endopeptidase (AEP) that may contribute to the formation of alpha-synuclein aggregates.

“In Parkinson’s, alpha-synuclein behaves much like Tau in Alzheimer’s,” Keqiang Ye, PhD and senior author of the study, said in a news release. “We reasoned that if AEP cuts Tau, it’s very likely that it will cut alpha-synuclein, too.”

The team observed that AEP cleaves the human form of the sticky protein alpha-synuclein, causing it to form clumps and accumulate in neurons. This affects the normal functioning and survival of dopaminergic neurons (neurons that produce dopamine) and the release of dopamine.

Dopamine is an important neurotransmitter in the brain and controls brain regions involved in movement control. Lack of dopamine leads to movement deficits, one of the most common symptoms of Parkinson’s disease.

Researchers found that AEP is highly activated in the brains of patients with Parkinson’s disease. AEP cleaves, or cuts into alpha-synuclein, starting the cascade of events leading to the loss of dopaminergic neurons.

To confirm the toxic role of alpha-synuclein after being cut by AEP, researchers promoted the expression of the AEP-induced alpha-synuclein fragment in the substantia nigra (a brain region rich in dopaminergic neurons) in mice. This led to both dopaminergic neuronal loss and movement defects in these animals. But inhibiting or preventing this alpha-synuclein fragment decreased the toxic effects.

Together, these results support the role of AEP as a trigger of abnormal alpha-synuclein accumulation within neurons and as a key player in the pathology of Parkinson’s disease.

According to Ye, there are other enzymes besides AEP that cut alpha-synuclein into toxic pieces in neurons, and the intact form of the protein is also able to aggregate and trigger neuronal damage. However, he believes the results of this study may help others not only to better understand how alpha-synuclein clumps are formed, but also lead to the development of new treatments for Parkinson’s disease.