Alzheimer’s disease (AD) and Parkinson’s disease (PD) both are distinct forms of dementia. They affect different regions in the cerebrum (or brain).
The two neurodegenerative diseases also have discrete genetic and environmental risk factors. However, years of experimental research by neurologists has formulated the hypothesis that the two diseases start to look similar at the biochemical level.
And the latest breakthrough serves as evidence for the theory, demonstrating the origins of the two debilitating conditions spurring from a common enzyme.
The breakthrough, by a team of scientists lead by Keqiang Ye at Emory University, USA, has lead to the discovery of a potential drug target for Parkinson’s.
About the Research & Team
Ye, PhD., and his team had previously identified an enzyme called asparagine endopeptidase (AEP), which had a role in making certain proteins more toxic. However, the mechanism that drives the neurodegeneration that ultimately leads to neuronal death of patients is still unknown.
However, they now have experimental evidence to suggest that the two diseases are linked through the enzyme AEP, making it a potential drug target. The team has also reportedly developed several potential therapeutic strategies with successful clinical trials.
Zhentao Zhang, Seong Su Kang, Xia Liu, Eun Hee Ahn, Zhaohui Zhang, Li He, P Michael Iuvone, Duc M Duong, Nicholas T Seyfried, Matthew J Benskey, Fredric P Manfredsson, Lingjing Jin, Yi E Sun, and Jian-Zhi Wang are the lead PhD researchers of the extensive study under Dr. Ye.
The ongoing experiment is being conducted in laboratories at Emory University.
The entire research work, including the complete experimental analysis with citations and references has been published, and can be found here.
Commonalities of Alzheimer’s & Parkinson’s
- The new discovery by the Team at Emory showed that in both AD and PD, a “sticky” protein formed toxic clumps in brain cells.
- In AD, the protein Tau (τ) is known to be responsible for forming these clumps in the form of “neurofibrillary” tangles. And in PD, the clumps are made of deposits of the protein α-synuclein (a.k.a. Lewy bodies). The Team had previously identified a common enzyme called asparagine endopeptidase (AEP) that makes τ more “sticky” and toxic.
- In a new Nature Structural and Molecular Biology paper, the Emory researchers claim that AEP acted in the same way toward α-synuclein.
- α-synuclein In Parkinson’s disease mirrored τ behavior in Alzheimer’s. Therefore it was concluded that if the enzyme AEP cut τ, it would cut α-synuclein, too.
Observations
The experiments were performed on human brain samples with PD and mouse brain samples. Samples of α-synuclein proteins were injected into mice brain samples to record effects.
A major observation was that a particular chunk of α-synuclein produced by AEP was present in samples of brain tissue from patients with PD, but not in control samples (regular samples).
In control brain samples AEP was confined to lysosomes (garbage disposal units of the biological cell).
But in PD samples, AEP was leaking out of the lysosomes to the rest of the cell. This explains how toxicity spreads throughout.
As per the research, the chunk of α-synuclein generated by AEP is more likely to aggregate into clumps than the full-length protein and is more toxic when introduced into cells or mouse brains.
Conclusion
Aggregation forms of the protein α-synuclein are clearly involved in the pathogenesis of diseases such as Parkinson’s and Alzheimer’s.
It has also been found that AEP cleaves human α-synuclein and triggers its aggregation and toxicity in the mice brain tissue. This leads to the conclusion that inhibiting AEP would counter PD in humans.
The Team is using these findings to test several potential drugs it discovered that would inhibit AEP in Parkinson’s animal brains first.
If the trials are successful, variants of the drug could be modeled and remodeled to target AEP in humans and destroy the aggregated Lewy bodies or sticky proteins.
