Nav: Home

Researchers identify mechanism that triggers a rare type of muscular dystrophy

January 29, 2020

Limb-girdle muscular dystrophy (LGMD) is the term given to a group of rare hereditary diseases characterised by the wasting and weakening of the hip and shoulder muscles.

LGMD type 1G (LGMD1G) is associated with two possible genetic mutations in a protein called hnRNPDL. Little is known about this protein, except that it exists in cells in three functional forms (isoforms) and that it may contain the genetic mutations linked to the disease.

A research team led by the Institute of Biotechnology and Biomedicine at the Universitat Autònoma de Barcelona (IBB-UAB) now explains the behaviour of this protein, its role in the cells and the phenotype caused by the genetic mutations associated with LGMD1G, in an article published in Cell Reports.

The research establishes that one of the protein's isoforms demonstrates a greater tendency to form amyloid fibrils - toxic protein aggregates - and this tendency to aggregate occurred significantly faster when the protein contained the genetic mutations related to the disease, which prevented it from performing correctly.

"For the first time we can provide solid proof of the effects genetic mutations have on the process of the hnRNPDL protein aggregation", affirms Salvador Ventura, IBB-UAB researcher and coordinator of the study. "Based on data obtained with the Drosophila fruit fly, we were able to suggest a possible mechanism for the disease: that it is the loss of protein function, once the aggregates are formed, that triggers the dystrophy. A hypothesis corroborated by the first data we are beginning to obtain with humans, and that opens the door to search for possible treatments".

Differential Behaviour

To conduct the study, researchers first analysed the presence and behaviour of the three isoforms in which the protein is found within the cells: with three, two or one protein domains, or independent regions. Then they studied the effects of the genetic mutations in the most common variant.

The isoform with two domains is most common in cells and, surprisingly for researchers, is also the one with the greatest tendency to form aggregates.

The researchers also saw that the isoform with three domains has a greater tendency to undergo a process known as phase separation, discovered a few years ago and of great biological importance, which could act as a prevention against the aggregations.

"What we have seen is that the more tendency towards phase separation, the less aggregates are formed. Until now, it was thought that phase separation was a process occurring after amyloid-type aggregation, and we have now seen that it is not always so", explains Salvador Ventura.

The study was conducted both in vitro and in human cells. It was also conducted on a transgenic model of the Drosophila fruit fly, in which the flies expressed their natural variant or each of the forms associated with the disease.
-end-
The research, in which IBB-UAB pre-doctoral researcher Cristina Batlle also participated, was conducted with the collaboration of researchers from the J. Paul Taylor research group of the St. Jude Children's Research Hospital in Memphis, Tennessee, and the research group of Xavier Salvatella at the Biomedical Research Institute of Barcelona.

Universitat Autonoma de Barcelona

Related Protein Articles:

Memory protein
When UC Santa Barbara materials scientist Omar Saleh and graduate student Ian Morgan sought to understand the mechanical behaviors of disordered proteins in the lab, they expected that after being stretched, one particular model protein would snap back instantaneously, like a rubber band.
Diets high in protein, particularly plant protein, linked to lower risk of death
Diets high in protein, particularly plant protein, are associated with a lower risk of death from any cause, finds an analysis of the latest evidence published by The BMJ today.
A new understanding of protein movement
A team of UD engineers has uncovered the role of surface diffusion in protein transport, which could aid biopharmaceutical processing.
A new biotinylation enzyme for analyzing protein-protein interactions
Proteins play roles by interacting with various other proteins. Therefore, interaction analysis is an indispensable technique for studying the function of proteins.
Substituting the next-best protein
Children born with Duchenne muscular dystrophy have a mutation in the X-chromosome gene that would normally code for dystrophin, a protein that provides structural integrity to skeletal muscles.
A direct protein-to-protein binding couples cell survival to cell proliferation
The regulators of apoptosis watch over cell replication and the decision to enter the cell cycle.
A protein that controls inflammation
A study by the research team of Prof. Geert van Loo (VIB-UGent Center for Inflammation Research) has unraveled a critical molecular mechanism behind autoimmune and inflammatory diseases such as rheumatoid arthritis, Crohn's disease, and psoriasis.
Resurrecting ancient protein partners reveals origin of protein regulation
After reconstructing the ancient forms of two cellular proteins, scientists discovered the earliest known instance of a complex form of protein regulation.
Sensing protein wellbeing
The folding state of the proteins in live cells often reflect the cell's general health.
Protein injections in medicine
One day, medical compounds could be introduced into cells with the help of bacterial toxins.
More Protein News and Protein Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Listen Again: The Power Of Spaces
How do spaces shape the human experience? In what ways do our rooms, homes, and buildings give us meaning and purpose? This hour, TED speakers explore the power of the spaces we make and inhabit. Guests include architect Michael Murphy, musician David Byrne, artist Es Devlin, and architect Siamak Hariri.
Now Playing: Science for the People

#576 Science Communication in Creative Places
When you think of science communication, you might think of TED talks or museum talks or video talks, or... people giving lectures. It's a lot of people talking. But there's more to sci comm than that. This week host Bethany Brookshire talks to three people who have looked at science communication in places you might not expect it. We'll speak with Mauna Dasari, a graduate student at Notre Dame, about making mammals into a March Madness match. We'll talk with Sarah Garner, director of the Pathologists Assistant Program at Tulane University School of Medicine, who takes pathology instruction out of...
Now Playing: Radiolab

What If?
There's plenty of speculation about what Donald Trump might do in the wake of the election. Would he dispute the results if he loses? Would he simply refuse to leave office, or even try to use the military to maintain control? Last summer, Rosa Brooks got together a team of experts and political operatives from both sides of the aisle to ask a slightly different question. Rather than arguing about whether he'd do those things, they dug into what exactly would happen if he did. Part war game part choose your own adventure, Rosa's Transition Integrity Project doesn't give us any predictions, and it isn't a referendum on Trump. Instead, it's a deeply illuminating stress test on our laws, our institutions, and on the commitment to democracy written into the constitution. This episode was reported by Bethel Habte, with help from Tracie Hunte, and produced by Bethel Habte. Jeremy Bloom provided original music. Support Radiolab by becoming a member today at Radiolab.org/donate.     You can read The Transition Integrity Project's report here.