Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Forgotten and lost - when proteins "shut down" our brain

19.02.2009
Max Planck scientists obtained important new insights into the structure and interaction of a protein relevant to Alzheimer’s disease

Which modules of the tau protein, in neurons of Alzheimer disease patients, may act in a destructive manner were investigated by researchers from the Max Planck Institute for Biophysical Chemistry (Göttingen) and the Max Planck Unit for Structural Molecular Biology (Hamburg) with the help of Nuclear Magnetic Resonance Spectroscopy (PLoS Biology, February 17, 2009).


Schematic view of the tau protein structure.
Image: Max Planck Institute for Biophysical Chemistry / Zweckstetter

Coordination becomes difficult, items disappear, keeping new information in the mind is impossible. Worldwide almost 30 million people suffer from Alzheimer’s disease, a neurodegenerative, irreversible ailment which starts with memory gaps and ends in helplessness and the loss of personality. The most critical factor in developing Alzheimer’s disease is age. Most cases occur after the age of 65.

Two hallmarks are typical for Alzheimer affected brains. One of them, located between nerve cells, is amyloid plaques - extracellular protein aggregates mainly composed of a protein named beta-amyloid. The other clue is intracellular tau fibrils. In the interplay with genetic factors, the latter contribute to a disordered communication within the cell. This triggers cell death.

But the tau protein is not only harmful. Quite the contrary is the case. In its normal non-pathogenic form tau binds to microtubules, long tubular cytoskeletal building blocks, which serve as "tracks" for intracellular transport. In patients afflicted by Alzheimer’s disease or similar dementia, tau is abnormally altered. In its pathogenic form tau possesses more phosphorylated amino acids than in its normal healthy counterpart. "Our interest was focussed on how certain phosphorylated residues alter the structure of tau in a way that it can not bind to microtubules anymore" explains Markus Zweckstetter at the Max Planck Institute for Biophysical Chemistry.

Exotic among proteins

Tau is special and with most biophysical methods, such as X-ray crystallography, not analyzable. Neither heat nor acid can harm the protein. Whereas most proteins fold to adopt the structure necessary for their function, tau can do it in the absence of folded structure, is very flexible and changes its form very rapidly.

With Nuclear Magnetic Resonance Spectroscopy the scientists where able to shed light on the structural properties of tau and followed its fast motions. For the first time detailed investigations of structural changes from a large almost unfolded protein where conducted. "The financial support was granted by the DFG Research Center "Molecular Physiology of the Brain" (CMPB) in Göttingen, the Volkswagen foundation and an institute overlapping Max Planck Society project, ‘Toxic protein conformation’ ", says Christian Griesinger, head of the department of NMR-based structural biology at the Max Planck Institute.

"We can directly observe which modules of the tau protein bind to microtubules. If the protein is equipped with more phosphates than usual we can see that in this case the binding becomes significantly weaker. Tau and microtubule proteins can no longer interact" summarizes Zweckstetter. As a direct consequence the transport along the microtubule "tracks" is disturbed and nerve cell endings do not grow.

The interplay with binding partners is also possibly broken down. "We now hold the tau protein in our hands and are able to look at the interaction with its binding partners in the cell in a very detailed way".

Tau as a drug target

Eckhard and Eva Mandelkow at the Max Planck Unit of Structural Molecular Biology in Hamburg are optimistic about using tau as a pharmaceutical target. On genetically altered mice, Eva Mandelkow and co-workers were able to show reversibility of the fatal consequences of tau aggregation. The next step for the Max Planck scientists would be the investigation of possible inhibitors which interact with the tau protein to prevent fibril formation.

Original work:

Marco D. Mukrasch, Stefan Bibow, Jegannath Korukottu, Sadasivam Jeganathan, Jacek Biernat, Christian Griesinger, Eckhard Mandelkow, Markus Zweckstetter
Structural Polymorphism of 441-residue tau at single residue resolution.
PLoS Biology, February 17, 2009.

Dr. Christina Beck | Max Planck Society
Further information:
http://www.mpg.de/english/

More articles from Life Sciences:

nachricht New risk factors for anxiety disorders
24.02.2017 | Julius-Maximilians-Universität Würzburg

nachricht Stingless bees have their nests protected by soldiers
24.02.2017 | Johannes Gutenberg-Universität Mainz

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Stingless bees have their nests protected by soldiers

24.02.2017 | Life Sciences

New risk factors for anxiety disorders

24.02.2017 | Life Sciences

MWC 2017: 5G Capital Berlin

24.02.2017 | Trade Fair News

VideoLinks
B2B-VideoLinks
More VideoLinks >>>