C9orf72 Protein Aggregation Pathway For Neurodegeneration

New processes for forming protein clumps that are characteristic of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) have been identified by scientists from Belgium, the UK and the US.

How these proteins, which can bind RNA in normal cells, stick together has remained elusive until recently, when scientists demonstrated that they de-mix from the watery substance inside cells, much like oil separates from water. Professor Ludo Van Den Bosch’s team shed light onto the molecular interactions behind the process in patients with defects in the C9orf72 gene.

Clumps of RNA-binding proteins occur naturally in normal neurons under times of stress in the form of stress granules (SGs), which precipitate from the water inside cells. However, in normal cells, the process of stress granule formation is tightly controlled, reversible and does not lead to disease.

Scientists previously believed that hydrophobic interactions – or the protein’s inability to mix with water – caused the formation of stress granules.

However, Dr. Steven Boeynaems and colleagues under guidance of Prof. Van Den Bosch of the Flanders Institute for Biotechnology, showed that in patients with defects in the C9orf72 gene, a different process can also cause this de-mixing, which precedes the formation of these toxic protein aggregates.

Mutation And Proteins Aggregation

Stress granules normally behave as liquid protein droplets within in a cell, while protein aggregates do not. The C9orf72 mutation causes neurons to produce small, abnormal and highly-charged toxic proteins, or peptides.

Yet, precisely how these peptides are toxic was not well-understood. The research team was able to observe in vitro that these peptides cause RNA-binding proteins to spontaneously stick together and change the dynamics of stress granules in cells, making them more like solids than liquids.

Prof. Van Den Bosch said:

“These observations give us more insight into the molecular process that leads to the clumping of RNA-binding protein in familial ALS and FTLD. It is believed that this process is an important step that occurs before the irreversible ‘sticking-together’ of the proteins, which is a pathological hallmark of these diseases. When enough of these clumps form, the neuron is unable to function and dies.”

A multidisciplinary approach was vital to the study.

University of Leuven’s Dr. Steven Boeynaems added:

“Based on our collaborative work, future studies could center around developing a molecular ‘antifreeze’ that prevents these liquid proteins from solidifying, thereby stopping protein aggregation and the death of neurons.”

Steven Boeynaems, Elke Bogaert, Denes Kovacs, Albert Konijnenberg, Evy Timmerman, Alex Volkov, Mainak Guharoy, Mathias De Decker, Tom Jaspers, Veronica H. Ryan, Abigail M. Janke, Pieter Baatsen, Thomas Vercruysse, Regina-Maria Kolaitis, Dirk Daelemans, J. Paul Taylor, Nancy Kedersha, Paul Anderson, Francis Impens, Frank Sobott, Joost Schymkowitz, Frederic Rousseau, Nicolas L. Fawzi, Wim Robberecht, Philip Van Damme, Peter Tompa, Ludo Van Den Bosch
Phase Separation ofC9orf72Dipeptide Repeats Perturbs Stress Granule Dynamics
Molecular Cell (2017). DOI: 10.1016/j.molcel.2017.02.013

Image: Nicoletta Baloyianni, Wellcome Images

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