A stronger twist to cytotoxic amyloid fibrils

October 24, 2017, University of Amsterdam
Amyloid fibrils. Credit: Universiteit van Amsterdam (UVA)

Researchers from Amsterdam and Enschede have for the first time performed a structural comparison of two types of amyloid fibrils that have been associated with Parkinson's disease. Using a combination of experimental methods they show that a cytotoxic C-terminal truncated form of the alpha-synuclein protein that is abundant in vivo, aggregates into more strongly twisted fibrils that are more exposed to water. The results have been published in the Journal of the American Chemical Society.

The research was carried out by PhD students Steven Roeters (Van 't Hoff Institute for Molecular Sciences, University of Amsterdam, under the supervision of professor Sander Woutersen) and Aditya Iyer (AMOLF, under the supervision of professor Vinod Subramaniam, Vrije Universiteit Amsterdam), in cooperation with Vladimir Kogan and professor Mireille Claessens from the University of Twente (UT).

Using a combination of techniques, among which , UV-circular dichroism, X-ray diffraction and , the researchers performed a structural analysis to explain the differences in the aggregation of wild-type alpha-synuclein (WT-αS) and the so-called C-terminal truncated form of the protein lacking 32 amino acids at the C-terminal end (1-108-αS). The latter has recently been observed by other groups to be quite common in vivo. It forms aggregates more rapidly and has been associated with a progressive form of Parkinson's disease. 

The researchers conclude that fibrils formed by 1-108-αS are more-strongly twisted and that - perhaps due to the stronger twist - their fibril core is more exposed to water. The distance between the hydrogen-bonded protein sheets within the fibril appears to be greater. These differences between 1-108-αS and WT-αS fibrils are even so pronounced that WT-αS monomers do not grow into fibrils seeded from short pieces of 1-108-αS fibrils.

By elucidating the key structural aspects of the two fibrillar species, especially of the more cytotoxic 1-108-αS fibrils, the researchers hope to provide clues contributing to an understanding of molecular mechanisms underlying Parkinson's and other related amyloid diseases.

Explore further: Tracing the path of Parkinson's disease proteins

More information: Aditya Iyer et al. C-terminal truncated α-synuclein fibrils contain strongly twisted β-sheets, Journal of the American Chemical Society (2017). DOI: 10.1021/jacs.7b07403

Related Stories

Tracing the path of Parkinson's disease proteins

August 4, 2017
As neurodegenerative disorders such as Parkinson's and Alzheimer's disease progress, misfolded proteins clump together in neurons, recruiting normal proteins in the cell to also misfold and aggregate. Cells in which this ...

Researchers unlock the molecular origins of Alzheimer's disease

September 6, 2017
A "twist of fate" that is minuscule even on the molecular level may cause the development of Alzheimer's disease, VCU researchers have found.

Closer look at proteins involved in Parkinson's disease reveals segment involved in amyloid formation

September 10, 2015
(Medical Xpress)—A team of scientists from several research centers in the U.S. has taken a closer look at α-synuclein, a protein that is abundant in the human brain, and which is also involved in the development of Parkinson's ...

Tiny changes in Parkinson's protein can have 'dramatic' impact on processes behind onset

August 29, 2016
Specific mutations in the protein associated with Parkinson's Disease, in which just one of its 140 building blocks is altered, can make a dramatic difference to processes which may lead to the condition's onset, researchers ...

Recommended for you

The eyes may have it, an early sign of Parkinson's disease

August 16, 2018
The eyes may be a window to the brain for people with early Parkinson's disease. People with the disease gradually lose brain cells that produce dopamine, a substance that helps control movement. Now a new study has found ...

First-of-its-kind Parkinson's biomarker guidelines invigorates drive for treatments

August 15, 2018
Parkinson's disease affects more than 4 million people worldwide, with numbers projected to double in the next few decades. With no known cure, there is a race for treatments to slow or stop the progression of the disease. ...

Study identifies chaperone protein implicated in Parkinson's disease

August 13, 2018
Reduced levels of a chaperone protein might have implications for the development and progression of neurodegenerative diseases such as Parkinson's disease and Lewy body dementia, according to new research from investigators ...

Function of gene mutations linked to neurological diseases identified

August 10, 2018
Several gene mutations have been linked to Parkinson's disease, but exactly how and where some of them cause their damage has been unclear. A new Yale study, published in the Journal of Cell Biology, shows that one of the ...

Biomarkers link fatigue in cancer, Parkinson's

August 9, 2018
Biological markers responsible for extreme exhaustion in patients with cancer have now been linked to fatigue in those with Parkinson's disease, according to new research from Rice University.

Researchers examining Parkinson's resilience

August 2, 2018
Diseases have a spectrum of risk, even those partially embedded in genes such as Parkinson's disease.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.