Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Parkinson’s Disease: New Insights into a Traveling Protein

05.01.2016

A laboratory study indicates that one of the main proteins involved in Parkinson’s disease pathology does not behave as a ‘prion’. Researchers led by Prof. Donato Di Monte report on this in the journal “BRAIN”.

In Parkinson’s disease, the protein “alpha-synuclein” aggregates within neurons of patients and appears to propagate across interconnected areas of the brain. How this happens remains largely unknown.


For the current study, DZNE researchera transferred the genetic blueprint of human alpha-synuclein into mice neurons (indicated by a dotted line). Source: DZNE/M. Helwig

It has been proposed that alpha-synuclein may behave like a “prion”: pathological forms of the protein may be capable of changing the conformation of normal alpha-synuclein and thus triggering its aggregation and neuron-to-neuron propagation (a phenomenon referred to as “seeding”).

Recent findings by scientists at the German Center for Neurodegenerative Diseases (DZNE) reveal that aggregation, spreading and pathology caused by alpha-synuclein do not necessarily involve prion-like seeding. Instead, they could be triggered by enhanced alpha-synuclein expression and trans-neuronal passage of monomeric and oligomeric forms of the protein. Researchers led by Prof. Donato Di Monte report on this in the journal “BRAIN”.

Abundant evidence underscores a critical role of the protein alpha-synuclein in the pathogenesis of Parkinson’s disease. In particular, alpha-synuclein is a major component of the intraneuronal inclusions, named Lewy bodies, that are progressively accumulated in the brains of patients with Parkinson’s disease.

Alpha-synuclein pathology often starts in a region of the lower brain called medulla oblongata from where it spreads upwardly toward midbrain and cortical areas. In the current study, sponsored in part by the Paul Foundation, DZNE researchers mimicked this phenomenon in mice.

With the aid of a tailor-made viral vector, they transferred the blueprint of the human alpha-synuclein gene specifically into neurons in the mouse medulla oblongata. These cells then began producing and accumulating relatively large amounts of the exogenous (human) alpha-synuclein.

Long-distance protein transmission

Using specific antibodies that recognize human alpha-synuclein, Di Monte and his colleagues tracked the spreading of this protein throughout the mouse brain over a period of 6 to 12 weeks. They also compared spreading and pathology in normal mice, which expressed both exogenous (human) and endogenous alpha-synuclein, versus mutant mice lacking their endogenous protein.

In both groups of animals, increased expression of human alpha-synuclein resulted in its progressive diffusion from the medulla oblongata toward more rostral brain regions. This protein spreading involved at least one trans-synaptic jump and followed a stereotypical pattern consistent with diffusion via anatomically interconnected pathways. Furthermore, accumulation of the spreading protein within recipient neurons was accompanied by evidence of neuronal damage.

Unlike prions

A prion-like seeding mechanism would predict that spreading of alpha-synuclein should be facilitated by interactions between abnormal forms of the protein generated within donor neurons and “uncorrupted” alpha-synuclein expressed within recipient cells. “In other words,” says Di Monte “we were expecting less efficient protein transmission and less pronounced pathology in mutant mice lacking endogenous alpha-synuclein. We were also expecting spreading and pathology to be associated with the accumulation of amyloidogenic alpha-synuclein; these are forms of the protein capable of producing insoluble fibrous aggregates.”

Contrary to these predictions, spreading of alpha-synuclein was enhanced rather than being counteracted by ablation of the endogenous protein in mutant mice. Furthermore, trans-neuronal passage of non-fibrillar alpha-synuclein species was responsible for protein diffusion and triggered neuronal pathology. The researcher explains, “We believe that these findings bear a number of important implications for disease pathogenesis. Not only can we conclude that long-distance diffusion of alpha-synuclein does not necessarily require the generation of prion-like species. Our data also reveal that spreading and pathology can be triggered by simple overexpression of the protein and are mediated, at least initially, by monomeric and/or oligomeric alpha-synuclein.”

Moving forward with studies on a “moving” protein

The possibility that alpha-synuclein may behave like a prion has raised the speculation that, similar to some prion diseases (for example, Creutzfeldt-Jakob disease), cases of Parkinson’s disease may arise from exposure to contagious protein species. Di Monte stresses: “There is absolutely no indication that Parkinson’s could be a contagious disease. In fact, an important contribution of our new study is that it emphasizes how critical aspects of Parkinson’s disease pathogenesis, such as neuron-to-neuron alpha-synuclein transmission and protein aggregation, can be explained by mechanisms that are not prion-like.”

Di Monte and his colleagues at the DZNE intend to continue working on alpha-synuclein and are particularly interested in elucidating how alpha-synuclein could be targeted to slow down or halt the pathologic and clinical progression of the disease.

Original publication
„Brain propagation of transduced α-synuclein involves nonfibrillar protein species and is enhanced in α-synuclein null mice“, Michael Helwig, Michael Klinkenberg, Raffaella Rusconi, Ruth E. Musgrove, Nour K. Majbour, Omar M.A. El-Agnaf, Ayse Ulusoy and Donato A. Di Monte, BRAIN, DOI: 10.1093/brain/awv376

The German Center for Neurodegenerative Diseases (DZNE) investigates the causes of diseases of the nervous system and develops strategies for prevention, treatment and care. It is an institution within the Helmholtz Association of German Research Centres with nine sites across Germany (Berlin, Bonn, Dresden, Göttingen, Magdeburg, Munich, Rostock/Greifswald, Tübingen and Witten). The DZNE cooperates closely with universities, their clinics and other research facilities.
Web: www.dzne.de/en  | Twitter: @dzne_en | Facebook: www.dzne.de/facebook 

Weitere Informationen:

http://www.dzne.de/en/about-us/public-relations/meldungen/2016/press-release-no-...

Dr. Marcus Neitzert | idw - Informationsdienst Wissenschaft

Further reports about: DZNE Parkinson’s Disease Protein mice lacking mutant mice neurons pathogenesis

More articles from Life Sciences:

nachricht The secret sulfate code that lets the bad Tau in
16.07.2018 | American Society for Biochemistry and Molecular Biology

nachricht Colorectal cancer risk factors decrypted
13.07.2018 | Max-Planck-Institut für Stoffwechselforschung

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: First evidence on the source of extragalactic particles

For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.

To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...

Im Focus: Magnetic vortices: Two independent magnetic skyrmion phases discovered in a single material

For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.

Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...

Im Focus: Breaking the bond: To take part or not?

Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.

A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...

Im Focus: New 2D Spectroscopy Methods

Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.

"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....

Im Focus: Chemical reactions in the light of ultrashort X-ray pulses from free-electron lasers

Ultra-short, high-intensity X-ray flashes open the door to the foundations of chemical reactions. Free-electron lasers generate these kinds of pulses, but there is a catch: the pulses vary in duration and energy. An international research team has now presented a solution: Using a ring of 16 detectors and a circularly polarized laser beam, they can determine both factors with attosecond accuracy.

Free-electron lasers (FELs) generate extremely short and intense X-ray flashes. Researchers can use these flashes to resolve structures with diameters on the...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Leading experts in Diabetes, Metabolism and Biomedical Engineering discuss Precision Medicine

13.07.2018 | Event News

Conference on Laser Polishing – LaP: Fine Tuning for Surfaces

12.07.2018 | Event News

11th European Wood-based Panel Symposium 2018: Meeting point for the wood-based materials industry

03.07.2018 | Event News

 
Latest News

Leading experts in Diabetes, Metabolism and Biomedical Engineering discuss Precision Medicine

13.07.2018 | Event News

Research finds new molecular structures in boron-based nanoclusters

13.07.2018 | Materials Sciences

Algae Have Land Genes

13.07.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>