ALS

U of T, University of Cambridge researchers find mechanism behind neuron death in ALS and dementia

noreen.rasbach — Thu, 19 Apr 2018 14:48:00 +0000

U of T, University of Cambridge researchers find mechanism behind neuron death in ALS and dementia

noreen.rasbach Thu, 04/19/2018 - 10:48

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Peter St George-Hyslop is director of the Tanz Centre for Research in Neurodegenerative Diseases and a professor in U of T's Faculty of Medicine

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Researchers at the University of Toronto and the University of Cambridge have identified the molecular mechanism that leads to the death of neurons in some types of ALS, or amyotrophic lateral sclerosis, and in a common form of frontotemporal dementia.

They have also uncovered novel therapeutic targets for these currently incurable diseases.

The journal Cell published the findings on Thursday.

A common characteristic of ALS and frontotemporal dementia is the clumping of misfolded RNA-binding proteins, including a protein called FUS, in the brain and spinal cord. In nerve cells, FUS proteins normally change back and forth from small liquid droplets (resembling oil droplets in water) to small gels (like jelly).

But in ALS and frontotemporal dementia, FUS proteins become permanently stuck as abnormally dense gels, trapping the RNA and making it unavailable for use. This damages nerve cells by blocking their ability to make the proteins needed for synaptic function and leads to the death of neurons in the brain and spinal cord.

“This was a very exciting set of experiments where we were able to apply cutting-edge tools from physics, chemistry and neurobiology to understand how the FUS protein normally works in nerve cells, and how it goes wrong in motor neuron disease and dementia,” said Peter St George-Hyslop, director of the Tanz Centre for Research in Neurodegenerative Diseases and a professor in U of T's Faculty of Medicine.

Read the research in the journal Cell

“For the past several years, evidence has been growing that understanding these phase transitions could significantly accelerate our ability to treat ALS,” said Dr. David Taylor, vice president, research at the ALS Society of Canada. “The work advances our understanding of this biology and reveals potential molecular targets for exploration, which might someday lead to the development of ALS treatments.”

Taylor notes that the research was possible in part through funding from the Ice Bucket Challenge and the ALS Society of Canada’s partnership with Brain Canada, and he said the findings are an example of why continued investment in research funding is vital.

The research was funded by the Canadian Institutes of Health Research, Wellcome Trust, European Research Council, Swiss National Science Foundation, and the ALS Society of Canada and Brain Canada (through the Canada Brain Research Fund, with support from Health Canada).

U of T joins international ALS project

ullahnor — Thu, 19 Jan 2017 16:05:02 +0000

U of T joins international ALS project

ullahnor Thu, 01/19/2017 - 11:05

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The project will map the DNA profiles of 15,000 people with ALS and create a global database of genetic information on the disease (photo by MV Maverick via Flickr)

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Dan Haves

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Ekaterina Rogaeva, a professor of neurology at the University of Toronto's Faculty of Medicine, is joining an international team of researchers trying to determine why some people develop ALS.

Known as Project MinE, the team helped discover the gene linked to ALS. It includes researchers in 17 nations, and now thanks to support from the ALS Society of Canada (ALS Canada), Canadian researchers have joined the team.

“About half of ALS heritability remains to be explained,” says Rogaeva (pictured left), who is also a researcher at the Tanz Centre for Research in Neurodegenerative Diseases.

In an effort to accelerate the search for a cure, Project MinE plans to map the DNA profiles of 15,000 people with ALS along with a control group of 7,500 people and create a global database of genetic information on the disease. With this new data, the hope is that researchers around the world can better target ALS by understanding the genetic mutations that lead to disease.

“Only together can we obtain sufficient power to analyze DNA samples from several thousand cases and controls so the ongoing whole genome sequencing of each MinE sample is critical,” say Rogaeva.

ALS, or amyotrophic lateral sclerosis, is a neurodegenerative disease that gradually paralyzes the body. Most people who are diagnosed with ALS die within two to five years of diagnosis as there is currently no effective treatment or cure. One thousand Canadians are diagnosed with ALS each year.

Project MinE will receive both the financial support of the ALS Canada and the scientific support of some of Canada’s leading ALS researchers. This is the first cross-Canada collaboration on ALS research and is one of the six projects funded by the ALS Ice Bucket Challenge.

ALS Canada and its research team hope to contribute up to 1,000 DNA profiles to the MinE Project. They are currently seeking federal funding, which would also allow the stored DNA profiles of Canadians with ALS to be added to the database.

“Having such a large sample set could improve understanding of the disease in order to provide the best medical advice to ALS carriers,” Rogaeva notes.

Hope for ALS patients? Discovery of a gene's function offers clues

sgupta — Mon, 28 Jul 2014 13:28:13 +0000

Hope for ALS patients? Discovery of a gene's function offers clues sgupta Mon, 07/28/2014 - 09:28

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Stephen Hawking (seen above at a NASA event in 2008), Canadian Sue Rodrigues and American baseball star Lou Gehrig are some of the most recognizable names of ALS patients (photo by NASA/Paul E. Alers via Flickr)

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Katie Babcock and Heidi Singer

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“This is an extremely important finding"

U of T researchers have found a missing link that helps to explain how ALS, one of the world’s most feared diseases, paralyses and ultimately kills its victims.

The breakthrough is helping them trace a path to a treatment or even a cure.

“ALS research has been taking baby steps for decades, but this has recently started changing to giant leaps,” said Karim Mekhail, an assistant professor in the Faculty of Medicine’s Department of Laboratory Medicine & Pathobiology.

“The disease is linked to a large number of genes, and previously, every time someone studied one of them, it took them off in a different direction. Nobody could figure out how they were all connected.”

Mekhail and his team discovered the function of a crucial gene called PBP1 or ATAXIN2 that’s often missing in ALS, also known as Lou Gehrig’s Disease. Learning how this gene functions has helped them connect a lot of dots.

“This is an extremely important finding that may help us to better understand and target the pathways involved in neurodegenerative disease,” said Dr. Lorne Zinman, an associate professor of medicine at U of T and medical director of the ALS/Neuromuscular Clinic at Sunnybrook Health Sciences Centre. “The next step will be to determine if this finding is applicable to patients with ALS.”

The key lies in a peculiarity of the human genome. It starts with the DNA, the blueprint that contains all our genetic information. The DNA passes its information to the RNA, which floats off to make proteins that help run our bodies. However, without ATAXIN2, the RNA fails to float away. It becomes glued to the DNA and forms RNA-DNA hybrids, said Mekhail. These hybrids gum up the works and stop other RNA from fully forming. Pieces of half-created RNA debris clutter the cell, and cause more hybrids.

“We think the debris and hybrids are on the same team in a never-ending Olympic relay race,” said Mekhail (pictured at right). “Over time there’s a vicious cycle building up. If we can find a way to disrupt that cycle, theoretically we can control or reverse the disease.”

On that front, Mekhail made a very surprising discovery: reducing calories to the minimum necessary amount stops the hybrids from forming in cells missing ATAXIN2. He and his team are studying whether a simple, non-toxic dietary restriction could be used with ALS patients, especially in the early stages or for those at risk of ALS.

Mekhail discovered the hybrids and missing genes in yeast cells and his results were published as the cover article for the July 28 edition of the journal Developmental Cell. Now his team is replicating this research on tissue from ALS patients – with very encouraging preliminary results.

"Within the next decade or two, I think there’s going to be a revolution in treatment for ALS and all kinds of brain disease,” he said. “These hybrids are going to play a role not just in ALS but in a lot of disease.”

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ALS

​U of T, University of Cambridge researchers find mechanism behind neuron death in ALS and dementia

Read more about Peter St George-Hyslop

Read the research in the journal Cell

U of T joins international ALS project

Hope for ALS patients? Discovery of a gene's function offers clues

U of T, University of Cambridge researchers find mechanism behind neuron death in ALS and dementia