One Enzyme To Rule Us All – Parkinson's And Alzheimer's Have Common Biochemical Origin

A sample from the brain of a person with Parkinson's Disease stained with an antibody that recognizes cleaved alpha-synuclein, but not the intact version. Zhang et al/NSMB 2017

Despite their considerable differences, the two most common neurodegenerative diseases – Parkinson's and Alzheimer's – both appear to involve the enzyme asparagine endopeptidase (AEP). The discovery has led to the creation of new drugs against Parkinson's disease, although they have yet to be tested in animals, let alone humans.

Clumps or tangles of the tau protein inside brain cells represent one of the distinguishing features of Alzheimer's disease. Parkinson's involves aggregations, known as Lewy bodies, of the alpha-synuclein protein. The effects are seen in distinct parts of the brain, so the consequences are different, and the known genetic and environmental risk factors are also dissimilar.

Nevertheless, Dr Keqiang Ye of Emory University has found that AEP contributes to both protein aggregations, a discovery that may help advance treatments. Ye demonstrated in 2014 that AEP cuts tau proteins, making them more sticky and likely to form. Now in Nature Structural and Molecular Biology, he has shown AEP has a similar effect on alpha-synuclein, a protein whose normal role we don't understand very well.

"In Parkinson's, alpha-synuclein behaves much like Tau in Alzheimer's," Ye said in a statement. "We reasoned that if AEP cuts Tau, it's very likely that it will cut alpha-synuclein too." The theory was confirmed when Ye produced an antibody that recognizes cleaved alpha-synuclein, but not the uncut molecule, and used it to check whether cutting had occurred in cells.

In healthy brains, AEP operates within cells' waste disposal systems, known as lysosomes, where enzymes digest molecules that are unwanted or no longer needed. However, in people with Parkinson's disease the AEP is found throughout the cell.

The problem is not simply that AEP sheers through alpha-synuclein, but that the remnants it leaves behind are more likely to form Lewy bodies. When injected into cultured cells or the brains of mice, the product is more toxic than the uncut version.

All this suggests that AEP inhibitors might reduce both Alzheimer's and Parkinson's disease, although if they affect the enzyme's function within the lysosomes, there could be a substantial price to pay. Considering the rise in frequency of both diseases in an aging population, the importance of such treatments is hard to overstate.

Such inhibitors have already been used in trials of animals with conditions analogous to Alzheimer's disease. They've done well, although caution is advised considering the long record of Alzheimer's treatments that didn't make the transition from success in animals to humans.

Ye's team plan to start testing AEP inhibitors on animals with Parkinson's disease (or conditions similar enough to serve as a model). Nevertheless, he cautions that AEP is unlikely to be the whole story, since other enzymes can also cut alpha-synuclein, with similar disastrous consequences.

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