All cells in our bodies make proteins, but sometimes they make mistakes, resulting in proteins that have the wrong shape. In a healthy body, protective mechanisms within the cells deal with the misshapen proteins so they don’t cause trouble, but when those mechanisms fail, the defective proteins can accumulate in clumps, making it difficult for cells to function correctly. A common feature of both familial and sporadic ALS is the accumulation of misfolded proteins in motor neurons. ALS usually develops over time, most often affecting people between the ages of 40 and 60. One theoretical cause of the disease is that motor neuron cells initially had protective mechanisms in place, but at some point, those processes could no longer keep up.

For many years, ALS researchers have been studying those protective mechanisms. They now know that guardian proteins called heat shock proteins handle the misbehaving proteins inside cells. While proteins are being manufactured in the cell, the heat shock proteins kind of hug them to protect them. But like chaperones at a school dance escorting misbehaving students to the principal’s office to be sent home, if heat shock proteins detect newly-made proteins that are not the right shape, they transport them another area of the cell to be either fixed up to behave properly or destroyed and ejected from the cell.

Researchers have identified drugs called heat shock protein inducers (HSP inducers) that can boost the production of heat shock proteins, however, so far, their effectiveness has been limited: “Stressed motor neuron cells are not very good at increasing production of heat shock proteins in the first place, and that deficiency gets worse as the disease progresses,” said Dr. Heather Durham, a neuroscientist at the Montreal Neurological Institute and Hospital (The Neuro). “Another issue is that some of the HSP inducers are too toxic, partly because they turn on the heat shock response all the time.”

Dr. Heather Durham and her colleagues at The Neuro have been studying heat shock proteins and looking for ways to achieve an ideal heat shock response in motor neurons. . They have discovered how to get a less toxic HSP inducer to work better in mouse neurons in tissue culture by combining it with another drug called a histone deacetylase (HDAC) inhibitor. “We discovered that by combining these two drugs, we could significantly boost the production of heat shock proteins,” said Dr. Durham. An HDAC inhibitor is a drug that relaxes the tightness of DNA to allow proteins to be made more easily.

Dr. Durham and three colleagues recently received ALS Canada-Brain Canada Arthur J. Hudson Translational Team Award of $1.74 million over four years to see if a promising HDAC inhibitor in combination with HSP inducers will help maintain an effective heat shock response in motor neurons. The team is excited to be collaborating with pharmaceutical companies that manufacture the drugs at this translational stage of the research spectrum.

Overall, they will pursue three areas of investigation:

  1. To identify an HDAC inhibitor with an acceptable safety profile that can access motor neuron cells and see if it plays a role by itself to maintain the heat shock response during disease progression in lab tissue culture models of ALS (ALS in a dish);
  2. To test an HDAC inhibitor drug in combination with HSP inducers and compare those results to how each drug works alone in lab cultured ALS motor neurons; and,
  3. To translate their findings in tissue cultures to ALS mice. They will examine if and how the drug treatment approaches work on the intended cellular processes, whether they can activate the heat shock response and improve protein quality control, and delay disease progression, including maintaining the connectivity of neurons and motor function. They will start with SOD1 ALS mice since these classes of drugs individually have shown some benefit and the protein quality control pathways for that form of ALS have been well characterized by previous research. They will also investigate the same effects in FUS and TDP-43 ALS mice.

“These drugs have been in development for decades, but a combination approach has never been tested,” Dr. Durham said. “We hope to confirm our significant findings in tissue culture models in ALS mice and see the full potential for these drugs to address protein quality control issues in ALS.” Pooling their expertise means that the researchers will not only be able to determine if the drug combination works, they will also be able to understand if and how it affects motor neurons.

“ALS is complex: It’s not just one disease, it’s many diseases, and we haven’t been able to make a sufficient impact on it yet,” said Dr. Durham. “I’m looking forward to finally getting a clear answer on whether we can use understandings about heat shock proteins as a basis for an effective treatment for ALS.”

If successful, this project will provide the proof of principle that drug companies will need to move forward with clinical trials using human volunteers in the future. Ultimately, this project could potentially lead to an exciting new treatment that can slow disease progression and improve quality of life for people living with ALS.

The ALS Canada-Brain Canada Arthur J. Hudson Translational Team Grant was named after Arthur J. Hudson, the co-founder of ALS Canada and is awarded in partnership with Brain Canada thanks to donations made during the Ice Bucket Challenge. It recognizes the spirit of collaboration by bringing ALS researchers together from different areas of expertise to accelerate the development of promising new therapeutic approaches.

Four ALS research experts from three Canadian universities are collaborating to pool their areas of expertise on this exciting research project over the next four years:

  • Dr. Heather Durham, a neuroscientist at the Montreal Neurological Institute and Hospital and principal investigator of this project, is an expert in self-defence mechanisms in motor neuron diseases, including the heat shock response, as well as protein degradation and misfolding processes.
  • Dr. Richard Robitaille, a neuroscientist at the Université de Montreal is an expert in measuring the connectivity of neurons to muscles at neuromuscular junctions.
  • Dr. Chantelle Sephton, a neuroscientist at the Cervo Brain Research Centre at Laval University, has developed a mouse model of FUS ALS and is an expert in how disease disrupts dendrites, the branched projections that allow neurons to connect to other neurons in the nervous system to transmit electrochemical signals.
  • Dr. Josephine Nalbantogulu, a neuroscientist at the Montreal Neurological Institute and Hospital, is an expert in the regulation of gene expression in the nervous system.

This research project is one of 12 funded by the ALS Canada Research Program in 2017 following a rigorous scientific assessment by a panel of global ALS experts. The panelists evaluated a larger pool of applications to identify the projects that are grounded in scientific excellence and have the potential to most quickly advance the field of ALS research in order to develop effective treatments.

ALS Canada is a registered charity that receives no government funding. Everything we do – from funding research to providing community-based support for people living with ALS – is possible only because of donor generosity and partnerships with provincial ALS Societies who contribute to the ALS Canada Research Program.

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Posted in: Research