Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

A slight twist with serious consequences

03.08.2009
Subtle structural changes can markedly affect one protein’s toxic impact, and may help explain the distinctive pathology of Huntington’s disease

Nobody is entirely sure what the huntingtin protein does when it’s operating normally, but the effects of its malfunction are all too clear: increasingly severe neurological deficits, affecting motor activity and memory and ultimately resulting in dementia.

Huntingtin typically contains an internal stretch of repeated glutamine residues, but this number increases—sometimes dramatically—in Huntington’s disease (HD) patients. This is accompanied by a marked structural change, with the protein aggregating into fibrous clumps within the brain known as amyloid deposits. It is unclear, however, what effect these have on neuronal health or the role they play in HD pathology.

In other plaque-forming diseases, such as prion disease and Alzheimer’s, these amyloid aggregates can assume multiple different structures with variable physiological effects. Now, RIKEN Brain Science Institute investigator Motomasa Tanaka and colleagues recently have found that huntingtin amyloids have similar properties1.

Temperature is known to affect protein folding, and initial experiments revealed subtle differences between huntingtin fibrils formed at body temperature versus 4 °C. Both samples were rich in structures known as â-sheets, but the lower temperature amyloids proved more fragile and detergent-sensitive, and exhibited higher affinity for labeling dyes. These distinct conformations could also be ‘amplified’ in cells; when amyloids formed at a particular temperature were introduced into cells expressing huntingtin with disease-specific numbers of repeats, they acted as seeds for the formation of larger aggregates with the same conformation. Surprisingly, the low-temperature aggregates were found to cause significantly higher levels of cell death than those formed at higher temperatures.

Tanaka’s team also found unexpected evidence that huntingtin aggregates isolated from a mouse model of HD assume different conformations depending on the region of the brain in which they formed. For example, amyloids from the striatum resembled low-temperature aggregates, while those isolated from the hippocampus were more similar to aggregates that formed at higher temperatures. These structural characteristics were also reflected in their relative cytotoxicity. Tanaka points out that the striatum is among the brain regions most vulnerable to HD, and suggests that “structural diversity of amyloid may dictate regional specificity of HD.”

These new structural insights help explain why different studies have yielded apparently contradictory findings about the extent of huntingtin fibril toxicity, although further investigation will be needed to determine the basis for this differential folding and the altered pathological impact of this alternate conformation. “Our current priority is to understand how the same polypeptide misfolds into distinct amyloid conformations,” says Tanaka.

Reference

1. Nekooki-Machida, Y., Kurosawa, M., Nukina, N., Ito, K., Oda, T. & Tanaka, M. Distinct conformations of in vitro and in vivo amyloids of huntingtin-exon1 show different cytotoxicity. Proceedings of the National Academy of Sciences USA 106, 9679–9684 (2009).

The corresponding author for this highlight is based at the RIKEN Tanaka Research Unit

Saeko Okada | Research asia research news
Further information:
http://www.rikenresearch.riken.jp/research/757/

More articles from Health and Medicine:

nachricht Vanishing capillaries
23.03.2017 | Technische Universität München

nachricht How prenatal maternal infections may affect genetic factors in Autism spectrum disorder
22.03.2017 | University of California - San Diego

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

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

Im Focus: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

Im Focus: Researchers Imitate Molecular Crowding in Cells

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

When Air is in Short Supply - Shedding light on plant stress reactions when oxygen runs short

23.03.2017 | Life Sciences

Researchers use light to remotely control curvature of plastics

23.03.2017 | Power and Electrical Engineering

Sea ice extent sinks to record lows at both poles

23.03.2017 | Earth Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>