Nav: Home

Molecular culprits of protein aggregation in ALS and FTLD

July 18, 2018

The mutated and aggregated protein FUS is implicated in two neurodegenerative diseases: amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Using a newly developed fruit fly model, researchers led by prof. Ludo Van Den Bosch (VIB-KU Leuven) have zoomed in on the protein structure of FUS to gain more insight into how it causes neuronal toxicity and disease.

ALS and FTLD are two different adult-onset neurodegenerative disorders in terms of the symptoms they cause and the neurons they affect. In ALS, the neurons that control muscle movement degenerate, resulting in progressive paralysis, while FTLD affects specific brain areas and causes dementia. Still, many patients present with symptoms of both diseases, so scientists and clinicians now believe they are actually on opposite ends of the same disease spectrum.

The overlap between ALS and FTLD is not only apparent in the clinic, but also when looking at the underlying disease mechanisms. FUS, for example, is implicated in both diseases. Mutations in the FUS gene cause familial ALS and aggregation of the FUS protein is observed in both ALS and FTLD.

From liquid droplets to insoluble aggregates

FUS normally resides in the nucleus of the cell, but relocates to stress granules in the cytoplasm upon cellular stress. Stress granules are basically liquid droplets in the cell, similar in content to the toxic protein aggregates found in ALS and FTLD, but different in that their assembly is dynamic and reversible.

Could these liquid droplets serve as stepping stones towards the formation of aggregates that are typical for disease? "We believe so," says Elke Bogaert, one of the researchers working with prof. Van Den Bosch. "Both FUS droplets and hydrogels have been shown to undergo a switch to irreversible fibrillarization in a test tube, but this process has not been studied in a cellular context".

Two protein domains

The team generated a fruit fly model of FUS toxicity to investigate the formation of liquid droplets in more detail. They identified a previously unrecognized synergistic effect between two different protein regions that mediate toxicity. "We found that the FUS protein that is misbehaving in ALS and FTLD can form liquid droplets via specific molecular interactions between hydrophobic and charged amino acids," explains Steven Boeynaems, another researcher involved in the study. One FUS protein domain was generally considered to mediate aggregation, but the new findings indicate that arginine residues in another region of the protein are also required for maturation of FUS in cellular stress granules.

Problems in flies, and humans?

Further experiments immediately hinted at the importance of this protein interaction. Boeynaems: "We showed that the interactions between exactly these two protein domains could explain toxicity in our fruit fly ALS model, suggesting how the protein may be misregulated in patients as well."

Prof. Ludo Van Den Bosch underscores the importance of figuring out the exact process of this so-called phase separation of droplets, that mature into aggregates: "Deciphering how and why proteins such as FUS start aggregating in the brain will be key to understand neurodegenerative diseases and could lead to novel therapeutic strategies. Our new findings highlight an important role for arginine-rich domains in the pathology of these proteins."
-end-
Publication

Molecular dissection of FUS points at synergistic effect of low-complexity domains in toxicity, Bogaert, Boeynaems, et al. 2018 Cell Reports

Questions from patients

A breakthrough in research is not the same as a breakthrough in medicine. The realizations of VIB researchers can form the basis of new therapies, but the development path still takes years. This can raise a lot of questions. That is why we ask you to please refer questions in your report or article to the email address that VIB makes available for this purpose: patienteninfo@vib.be. Everyone can submit questions concerning this and other medically-oriented research directly to VIB via this address.

VIB (the Flanders Institute for Biotechnology)

Related Protein Articles:

Hi-res view of protein complex shows how it breaks up protein tangles
A new, high-resolution view of the structure of Hsp104 (heat shock protein 104), a natural yeast protein nanomachine with six subunits, may show news ways to dismantle harmful protein clumps in disease.
Breaking the protein-DNA bond
A new Northwestern University study finds that unbound proteins in a cell break up protein-DNA bonds as they compete for the single-binding site.
FASEB Science Research Conference: Protein Kinases and Protein Phosphorylation
This conference focuses on the biology of protein kinases and phosphorylation signaling.
Largest resource of human protein-protein interactions can help interpret genomic data
An international research team has developed the largest database of protein-to-protein interaction networks, a resource that can illuminate how numerous disease-associated genes contribute to disease development and progression.
STAT2: Much more than an antiviral protein
A protein known for guarding against viral infections leads a double life, new research shows, and can interfere with cell growth and the defense against parasites.
A protein makes the difference
It is well-established knowledge that blood vessels foster the growth of tumors.
Nuclear protein causes neuroblastoma to become more aggressive
Aggressive forms of neuroblastoma contain a specific protein in their cells' nuclei that is not found in the nuclei of more benign forms of the cancer, and the discovery, made through research from the University of Rochester Medical Center, could lead to new forms of targeted therapy.
How a protein could become the next big sweetener
High-fructose corn syrup and sugar are on the outs with calorie-wary consumers.
High animal protein intake associated with higher, plant protein with lower mortality rate
The largest study to examine the effects of different sources of dietary protein found that a high intake of proteins from animal sources -- particularly processed and unprocessed red meats -- was associated with a higher mortality rate, while a high intake of protein from plant sources was associated with a lower risk of death.
Protein in, ammonia out
A recent study has compiled and analyzed data from 25 previous studies.

Related Protein Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Bias And Perception
How does bias distort our thinking, our listening, our beliefs... and even our search results? How can we fight it? This hour, TED speakers explore ideas about the unconscious biases that shape us. Guests include writer and broadcaster Yassmin Abdel-Magied, climatologist J. Marshall Shepherd, journalist Andreas Ekström, and experimental psychologist Tony Salvador.
Now Playing: Science for the People

#513 Dinosaur Tails
This week: dinosaurs! We're discussing dinosaur tails, bipedalism, paleontology public outreach, dinosaur MOOCs, and other neat dinosaur related things with Dr. Scott Persons from the University of Alberta, who is also the author of the book "Dinosaurs of the Alberta Badlands".