Enzyme Slices Off Protein Chunks That End up Toxic, Contributing to Parkinson’s and Alzheimer’s, Study Reports

Enzyme Slices Off Protein Chunks That End up Toxic, Contributing to Parkinson’s and Alzheimer’s, Study Reports

An enzyme called asparagine endopeptidase contributes to Parkinson’s as well as Alzheimer’s by slicing off fragments of proteins that end up being toxic, a study reports.

Previous researched showed that the enzyme, also known as AEP, plays a role in Alzheimer’s. The new study indicates it plays a role in Parkinson’s, too.

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

An accumulation of faulty proteins in neurons triggers neurodegenerative disorders such as Parkinson’s and Alzheimer’s. A hallmark of Alzheimer’s is the formation of tau protein clumps, while in Parkinson’s it is alpha-synuclein clumps.

The mechanisms underlying these defects have yet to be fully understood, but researchers have identified a strong candidate: the AEP enzyme.

“In Parkinson’s, alpha-synuclein behaves much like Tau in Alzheimer’s,” Dr. Keqiang Ye, the 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 discovered that AEP slices off pieces of the human form of alpha-synuclein, leading to it clumping and accumulating in neurons. This affects the normal functioning and survival of neurons that produce the neurotransmitter dopamine. Loss of dopamine-producing neurons contributes to movement problems, a common symptom of Parkinson’s.

AEP was over-active in brain samples of Parkinson’s patients, researchers said. This supports the notion that it slices off fragments of alpha-synuclein, which end up being toxic, triggering the loss of dopaminergic neurons.

To confirm the toxic role of the alpha-synuclein pieces the enzyme cuts off, researchers triggered  the expression of alpha-synuclein fragments in a brain region in mice. The region, which is rich in dopamine-producing neurons, is called the substantia nigra.

The mice ended up with both dopamine neuron loss and movement defects. Importantly, the symptoms decreased when researchers inhibited the alpha-synuclein fragments.

Together, the results support the notion that AEP triggers an abnormal accumulation of alpha-synuclein in neurons and is a key player in both Parkinson’s and Alzheimer’s.

Ye said AEP is not the only enzyme that slices alpha-synuclein into toxic pieces in neurons. He also noted that the intact form of the protein is also able to clump, triggering neuron damage.

But the study offers additional insight into what causes faulty protein clumps to form in the brain, he said.

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