Nature Structural and Molecular Biology—AEP可能是治疗帕金森病的潜在药物靶点
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.