Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Drug discovery: Alzheimer's and Parkinson's spurred by same enzyme

04.07.2017

AEP protease acts on amyloid, tau and now alpha-synuclein

Alzheimer's disease and Parkinson's disease are not the same. They affect different regions of the brain and have distinct genetic and environmental risk factors.


This is a Parkinson's disease brain sample, stained with an antibody that only recognizes the N103 chunk of alpha-synuclein, which is generated through cleavage by AEP.

Credit: From Zhang et al NSMB (2017).

But at the biochemical level, these two neurodegenerative diseases start to look similar. That's how Emory scientists led by Keqiang Ye, PhD, landed on a potential drug target for Parkinson's.

In both Alzheimer's (AD) and Parkinson's (PD), a sticky protein forms toxic clumps in brain cells. In AD, the troublemaker inside cells is called tau, making up neurofibrillary tangles. In PD, the sticky protein is alpha-synuclein, forming Lewy bodies.

Ye and his colleagues had previously identified an enzyme (asparagine endopeptidase or AEP) that trims tau in a way that makes it more sticky and toxic. Drugs that inhibit AEP have beneficial effects in Alzheimer's animal models.

In a new Nature Structural and Molecular Biology paper, Emory researchers show that AEP acts in the same way toward alpha-synuclein.

"In Parkinson's, alpha-synuclein behaves much like Tau in Alzheimer's," Ye says. "We reasoned that if AEP cuts Tau, it's very likely that it will cut alpha-synuclein too."

A particular chunk of alpha-synuclein produced by AEP's scissors can be found in samples of brain tissue from patients with PD, but not in control samples, Ye's team found.

In control brain samples AEP was confined to lysosomes, parts of the cell with a garbage disposal function. But in PD samples, AEP was leaking out of the lysosomes to the rest of the cell.

The researchers also observed that the chunk of alpha-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. In addition, alpha-synuclein mutated so that AEP can't cut it is less toxic.

Ye cautions that AEP is not the only enzyme that cuts alpha-synuclein into various toxic pieces, and the full-length alpha-synuclein protein is still able to aggregate and cause harm. Nevertheless, he says his team is moving on to testing drugs that inhibit AEP in Parkinson's animal models.

###

First author Zhentao Zhang, MD, PhD, a former postdoc with Ye, is now at Wuhan University in China.

At Emory, the laboratories of P. Michael Iuvone, PhD in the Department of Ophthalmology and Nick Seyfried, PhD in the Department of Biochemistry contributed to the paper. Lingjing Jin, MD at Shanghai Tongji Hospital and Jian-Zhi Wang, MD, Key Laboratory of Ministry of Education of China for Neurological Disorders also contributed to the paper.

The research was supported by the Michael J. Fox Foundation, the National Natural Science Foundation of China and the National Eye Institute (P30EY006360 and R01EY004864).

Holly Korschun | EurekAlert!

More articles from Life Sciences:

nachricht New catalyst controls activation of a carbon-hydrogen bond
21.11.2017 | Emory Health Sciences

nachricht The main switch
21.11.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Nanoparticles help with malaria diagnosis – new rapid test in development

The WHO reports an estimated 429,000 malaria deaths each year. The disease mostly affects tropical and subtropical regions and in particular the African continent. The Fraunhofer Institute for Silicate Research ISC teamed up with the Fraunhofer Institute for Molecular Biology and Applied Ecology IME and the Institute of Tropical Medicine at the University of Tübingen for a new test method to detect malaria parasites in blood. The idea of the research project “NanoFRET” is to develop a highly sensitive and reliable rapid diagnostic test so that patient treatment can begin as early as possible.

Malaria is caused by parasites transmitted by mosquito bite. The most dangerous form of malaria is malaria tropica. Left untreated, it is fatal in most cases....

Im Focus: A “cosmic snake” reveals the structure of remote galaxies

The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.

Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...

Im Focus: Visual intelligence is not the same as IQ

Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.

That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...

Im Focus: Novel Nano-CT device creates high-resolution 3D-X-rays of tiny velvet worm legs

Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.

During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....

Im Focus: Researchers Develop Data Bus for Quantum Computer

The quantum world is fragile; error correction codes are needed to protect the information stored in a quantum object from the deteriorating effects of noise. Quantum physicists in Innsbruck have developed a protocol to pass quantum information between differently encoded building blocks of a future quantum computer, such as processors and memories. Scientists may use this protocol in the future to build a data bus for quantum computers. The researchers have published their work in the journal Nature Communications.

Future quantum computers will be able to solve problems where conventional computers fail today. We are still far away from any large-scale implementation,...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Ecology Across Borders: International conference brings together 1,500 ecologists

15.11.2017 | Event News

Road into laboratory: Users discuss biaxial fatigue-testing for car and truck wheel

15.11.2017 | Event News

#Berlin5GWeek: The right network for Industry 4.0

30.10.2017 | Event News

 
Latest News

Previous evidence of water on mars now identified as grainflows

21.11.2017 | Physics and Astronomy

NASA's James Webb Space Telescope completes final cryogenic testing

21.11.2017 | Physics and Astronomy

New catalyst controls activation of a carbon-hydrogen bond

21.11.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>