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 Complete skin regeneration system of fish unraveled
24.04.2018 | Tokyo Institute of Technology

nachricht Scientists generate an atlas of the human genome using stem cells
24.04.2018 | The Hebrew University of Jerusalem

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: BAM@Hannover Messe: innovative 3D printing method for space flight

At the Hannover Messe 2018, the Bundesanstalt für Materialforschung und-prüfung (BAM) will show how, in the future, astronauts could produce their own tools or spare parts in zero gravity using 3D printing. This will reduce, weight and transport costs for space missions. Visitors can experience the innovative additive manufacturing process live at the fair.

Powder-based additive manufacturing in zero gravity is the name of the project in which a component is produced by applying metallic powder layers and then...

Im Focus: Molecules Brilliantly Illuminated

Physicists at the Laboratory for Attosecond Physics, which is jointly run by Ludwig-Maximilians-Universität and the Max Planck Institute of Quantum Optics, have developed a high-power laser system that generates ultrashort pulses of light covering a large share of the mid-infrared spectrum. The researchers envisage a wide range of applications for the technology – in the early diagnosis of cancer, for instance.

Molecules are the building blocks of life. Like all other organisms, we are made of them. They control our biorhythm, and they can also reflect our state of...

Im Focus: Spider silk key to new bone-fixing composite

University of Connecticut researchers have created a biodegradable composite made of silk fibers that can be used to repair broken load-bearing bones without the complications sometimes presented by other materials.

Repairing major load-bearing bones such as those in the leg can be a long and uncomfortable process.

Im Focus: Writing and deleting magnets with lasers

Study published in the journal ACS Applied Materials & Interfaces is the outcome of an international effort that included teams from Dresden and Berlin in Germany, and the US.

Scientists at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) together with colleagues from the Helmholtz-Zentrum Berlin (HZB) and the University of Virginia...

Im Focus: Gamma-ray flashes from plasma filaments

Novel highly efficient and brilliant gamma-ray source: Based on model calculations, physicists of the Max PIanck Institute for Nuclear Physics in Heidelberg propose a novel method for an efficient high-brilliance gamma-ray source. A giant collimated gamma-ray pulse is generated from the interaction of a dense ultra-relativistic electron beam with a thin solid conductor. Energetic gamma-rays are copiously produced as the electron beam splits into filaments while propagating across the conductor. The resulting gamma-ray energy and flux enable novel experiments in nuclear and fundamental physics.

The typical wavelength of light interacting with an object of the microcosm scales with the size of this object. For atoms, this ranges from visible light to...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Invitation to the upcoming "Current Topics in Bioinformatics: Big Data in Genomics and Medicine"

13.04.2018 | Event News

Unique scope of UV LED technologies and applications presented in Berlin: ICULTA-2018

12.04.2018 | Event News

IWOLIA: A conference bringing together German Industrie 4.0 and French Industrie du Futur

09.04.2018 | Event News

 
Latest News

Quantum Technology for Advanced Imaging – QUILT

24.04.2018 | Information Technology

AWI researchers measure a record concentration of microplastic in arctic sea ice

24.04.2018 | Earth Sciences

Complete skin regeneration system of fish unraveled

24.04.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>