Proteins are the workhorses inside cells, responsible for almost all cellular functions. To perform their tasks correctly, they must fold into the right 3D shapes. If they take on the wrong shape, they can stick together and form clumps. If the misfolded proteins are not removed by protective mechanisms in cells, they can cause toxic effects.

Prion diseases are neurodegenerative diseases that involve misfolding and clumping of proteins in neuron cells that spread throughout the nervous system when protective cellular mechanisms don’t function properly. Well-known prion diseases include mad cow disease in cattle, scrapie in sheep and Creutzfeldt-Jakob disease in humans.

Since 2001, Dr. Marco Prado, a scientist at the Robarts Research Institute at Western University in London, Ontario, has been studying proteins as they relate to prion diseases. Specifically, he wants to know how abnormal protein behaviours play roles in neurodegenerative diseases in mice. One of the proteins he has been investigating is TDP-43, a protein that is known to misfold and clump in the vast majority of ALS cases, causing toxic effects to motor neurons. “All the time, billions of cells in our bodies deal with proteins that are behaving abnormally, but healthy cells have a way to defend themselves by degrading abnormal proteins,” said Dr. Prado. “If that quality control system becomes overwhelmed by a misbehaving protein like TDP-43, the effect is toxic and motor neurons start to die.”

Another scientist on the Western campus, Dr. Martin Duennwald, has been studying the quality control mechanisms that deal with abnormal proteins in yeast. Those mechanisms involve heat shock proteins that work like guardians inside cells. In a healthy body, heat shock proteins can fix misfolded proteins so they can work again, or, if that doesn’t work, ensure that they are destroyed. One hypothesis about how ALS occurs is that the heat shock proteins are not able to keep up with their job to manage misbehaving proteins like TDP-43. Dr. Duennwald has discovered that a protein involved in the heat shock response called stress induced phosphoprotein 1 (STI1) can reduce TDP-43 abnormalities in yeast, but that effect has not yet been tested in animal research.

With a project grant of $125,000 from the ALS Canada Research Program, the two scientists will combine their expertise with Dr. Flavio Beraldo, a scientist who has worked with Dr. Prado for many years creating genetically modified mice and studying how abnormal protein processes play a role in neurodegenerative diseases. In this project, the three scientists will combine their expertise to investigate whether STI1 plays a similar guardianship role in mice.

First, they will create mice with abnormal TDP-43 protein to have higher and lower levels of STI1 and see if changing STI1 levels has an impact on ALS disease progression. “We are the only laboratory in the world with access to mice that have been genetically modified to have more or less STI1 protein,” said Dr. Prado. “The mouse is an excellent model for our research because its genome is very similar to the human genome. STI1 in mice is almost identical to STI1 in humans,” he explained.

Dr. Prado thinks that mice with more STI1 will show less degeneration of motor neurons and that they will survive longer. If he and his colleagues find that more STI1 does protect spinal cord neurons from TDP-43 toxicity, they will also try to uncover the underlying mechanisms that make that possible. “If more STI1 does play a protective role, we want to understand exactly how that works, to pave the way for future research that may look for new ways to increase STI1 in people living with ALS to help slow disease progression and improve quality of life,” he said.

Dr. Prado hopes that this project will provide valuable insights that could lead to new treatments for people living with ALS in the future, such as designing drugs that could mimic what STI1 does or gene therapies that could instruct motor neurons to express more STI1 protein.

This research project is one of 12 funded by the ALS Canada Research Program in 2017 following a rigorous scientific assessment by panels of global ALS experts. The panellists 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.

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Posted in: Research