University of Toronto researchers discover RNA-binding proteins play important role.
University of Toronto (U of T) researchers are proposing a new way of understanding Amyotrophic Lateral Sclerosis (ALS), the devastating and incurable neurological disease. Their findings, published today in the journal Neuron, could be a major milestone on the path to a treatment for both ALS and dementia.
By delving into a previously overlooked corner of ALS research, Professor Peter St. George-Hyslop and his team discovered a new way in which the disease kills nerve cells.
“These are dreadful diseases — the more we know about how they work, the faster we’ll find treatments or even a cure,” says St. George-Hyslop, Director of U of T’s Tanz Centre for Research in Neurodegenerative Diseases.
Many cases of ALS are sparked by a toxic build-up of certain proteins, which cause neurons in the brain and spinal cord to die. Paralysis and suffocation result, meaning that few people live more than five years with an ALS diagnosis. Over the last decade, mutations that cause ALS have been found in a growing number of genes that encode RNA-binding proteins. The protein they create commonly builds up inside the diseased brain and spinal cords in ALS patients. Until now, scientists haven’t thought this build-up was important to the disease process because it looked different from the types of protein accumulations — such as tau, amyloid and alpha synuclein — that are clearly toxic and always found in patients with Alzheimer’s, Parkinson’s and some forms of dementia.
Several years ago, St. George-Hyslop decided to take a closer look at these seemingly innocuous protein accumulations. Working with Tanz researcher Tetsuro Murakami and with colleagues at the University of Cambridge and Columbia University, they focused initially on the FUS protein, and discovered that these abnormal clumps could actually be a very important player in causing nerve cell damage and ALS.
The FUS protein normally plays a key role in the healthy functioning of neurons, which transmit nerve signals in the brain and spinal cord. However, FUS and other proteins in its RNA-binding class seem to operate differently from many other cellular proteins. St. George-Hyslop’s team showed that FUS protein has the very unusual ability to morph from a liquid to a gel that resembles Jell-O. The gel form of FUS allows it to collect other cellular components that are necessary to make new proteins, and delivers them in a compact, concentrated form to the outer edges of the neurons. After reaching its destination, the gel melts into liquid, releasing the cellular components and allowing protein synthesis to occur. Its ability to repeatedly cycle between liquid and gel, allows FUS to rapidly and discreetly control protein synthesis in specific parts of the cell. This ability is key to keeping big cells like spinal cord neurons — which can be more than a metre long — in a healthy state.
The research team found that mutations in FUS changed the property of FUS protein so that it tends to form very dense gels that do not easily re-melt and release their cargo appropriately. As a result, it’s unable to deliver the tools necessary for the neurons to stay healthy and do their job.
“This kills the nerve by throttling it and preventing it from making new protein in the parts of the cell that desperately need it,” says St. George-Hyslop, who is also a Cambridge professor. “The mutations force the gelling process to go further than it should have gone.”
The next step is for researchers to find ways to prevent the solidification of the gel, or to reverse the hardening process, offering a key to a future drug to treat ALS and frontotemporal dementia — another disease in which the protein is active.
The discovery has implications for other, more common forms of ALS that have accumulations of other over-gelled RNA binding proteins.
Source: Heidi Singer – University of Toronto
Image Source: The image is in the public domain
Original Research: Full open access research for “ALS/FTD Mutation-Induced Phase Transition of FUS Liquid Droplets and Reversible Hydrogels into Irreversible Hydrogels Impairs RNP Granule Function” by Tetsuro Murakami, Seema Qamar, Julie Qiaojin Lin, Gabriele S. Kaminski Schierle, Eric Rees, Akinori Miyashita, Ana R. Costa, Roger B. Dodd, Fiona T.S. Chan, Claire H. Michel, Deborah Kronenberg-Versteeg, Yi Li, Seung-Pil Yang, Yosuke Wakutani, William Meadows, Rodylyn Rose Ferry, Liang Dong, Gian Gaetano Tartaglia, Giorgio Favrin, Wen-Lang Lin, Dennis W. Dickson, Mei Zhen, David Ron, Gerold Schmitt-Ulms, Paul E. Fraser, Neil A. Shneider, Christine Holt, Michele Vendruscolo, Clemens F. Kaminski, and Peter St George-Hyslop in Neuron. Published online October 29 2015 doi:10.1016/j.neuron.2015.10.030
Abstract
ALS/FTD Mutation-Induced Phase Transition of FUS Liquid Droplets and Reversible Hydrogels into Irreversible Hydrogels Impairs RNP Granule Function
Highlights
•FUS phase transitions between monomer, liquid droplet, and hydrogel states
•FUS mutants induce further phase transition into irreversible fibrillar hydrogels
•Irreversible hydrogels sequester RNP cargo and impair RNP granule function
•Formation of non-amyloid fibrillar hydrogels provides a compelling causative mechanism for neurodegeneration
Summary
The mechanisms by which mutations in FUS and other RNA binding proteins cause ALS and FTD remain controversial. We propose a model in which low-complexity (LC) domains of FUS drive its physiologically reversible assembly into membrane-free, liquid droplet and hydrogel-like structures. ALS/FTD mutations in LC or non-LC domains induce further phase transition into poorly soluble fibrillar hydrogels distinct from conventional amyloids. These assemblies are necessary and sufficient for neurotoxicity in a C. elegans model of FUS-dependent neurodegeneration. They trap other ribonucleoprotein (RNP) granule components and disrupt RNP granule function. One consequence is impairment of new protein synthesis by cytoplasmic RNP granules in axon terminals, where RNP granules regulate local RNA metabolism and translation. Nuclear FUS granules may be similarly affected. Inhibiting formation of these fibrillar hydrogel assemblies mitigates neurotoxicity and suggests a potential therapeutic strategy that may also be applicable to ALS/FTD associated with mutations in other RNA binding proteins.
“ALS/FTD Mutation-Induced Phase Transition of FUS Liquid Droplets and Reversible Hydrogels into Irreversible Hydrogels Impairs RNP Granule Function” by Tetsuro Murakami, Seema Qamar, Julie Qiaojin Lin, Gabriele S. Kaminski Schierle, Eric Rees, Akinori Miyashita, Ana R. Costa, Roger B. Dodd, Fiona T.S. Chan, Claire H. Michel, Deborah Kronenberg-Versteeg, Yi Li, Seung-Pil Yang, Yosuke Wakutani, William Meadows, Rodylyn Rose Ferry, Liang Dong, Gian Gaetano Tartaglia, Giorgio Favrin, Wen-Lang Lin, Dennis W. Dickson, Mei Zhen, David Ron, Gerold Schmitt-Ulms, Paul E. Fraser, Neil A. Shneider, Christine Holt, Michele Vendruscolo, Clemens F. Kaminski, and Peter St George-Hyslop in Neuron. Published online October 29 2015 doi:10.1016/j.neuron.2015.10.030
