A protein called TDP-43 is usually found inside the cell nucleus where it plays an essential role in regulating many cellular processes. But in 97 per cent of people with ALS and nearly half of the people with frontotemporal dementia, TDP-43 is found outside the cell nucleus in an area called the cytoplasm. Understanding why TDP-43 moves to the cytoplasm and tends to aggregate or clump up there, and how those behaviours lead to the development of ALS, is a crucial area of investigation in ALS research.

With a $125,000 project grant from the ALS Canada Research Program in 2018, Dr. Christine Vande Velde at l’Université de Montreal will study the behaviour of TDP-43 and its relationship to another protein called hnRNP A1 which is a cousin to TDP-43, and her team discovered to also be involved in ALS disease processes. New understandings about the relationship between hnRNP A1 and TDP-43 may lead to the development of new therapies and a biomarker to measure disease progression or the effectiveness of new treatments in clinical trials in the future.

Conflicting results led to a discovery

Several years ago, two students in Dr. Vande Velde’s lab at l’Université de Montréal got conflicting results in lab experiments while trying to detect hnRNP A1. They used different tools in their lab tests, which may have been the issue. But Dr. Vande Velde suspected something else might explain their findings. She assigned a student to work full time to investigate.

Following that instinct led to the discovery that a previously unstudied abnormal protein called heterogeneous nuclear ribonucleoprotein A1B (hnRNP A1B) may play a role in ALS. “It is a slightly larger version of a very abundant and important protein called hnRNP A1 that is mutated in rare cases of familial ALS,” said Dr. Vande Velde. “We were surprised to find that people with ALS have more of this larger protein in their motor neurons and that it is more often stuck in the cytoplasm, compared to people without ALS.”

“HnRNP A1B is a bit bigger than the more abundant A1 variant of the protein, so we think that is what causes it to clump up more,” said Dr. Vande Velde. “Until now, the longer protein has been largely ignored as most scientists have been investigating the shorter form.” She also observed that the clumps of hnRNP A1B were distinct from the clumps of TDP-43.

Dr. Vande Velde and her team were inspired when they found a relationship between TDP-43 and hnRNP A1 in cell experiments and animal models of sporadic ALS, the most common form of the disease. They discovered that the presence of TDP-43 in the cytoplasm caused the longer form to accumulate there as well.

Collaborations make a difference

For the discovery, Dr. Vande Velde collaborated with a cancer researcher named Dr. Benoit Chabot at the Université de Sherbrooke who provided the cell lines. “He is one of the few researchers in the world who has ever studied this long form of the protein,” said Dr. Vande Velde. “He has been a wonderful collaborator. He provided us cell lines with either the short or long version of the protein and used his expertise to shed light on the molecular mechanism that gives rise to it. He really helped us show that the formation of hnRNP A1B depended on TDP-43.”

For the current project, Dr. Vande Velde invited Dr. Marlene Oeffinger at Institut de Recherches Cliniques de Montréal (IRCM), an expert in the unique structures that hnRNP A1B may form, to join her as a co-investigator. Their research teams will study the function of hnRNP A1B and its relationship to TDP-43 in ALS disease processes that result in toxicity to motor neurons. “I believe in collaboration. I’m not very shy about reaching out to other researchers,” Dr. Vande Velde said. “Dr. Oeffinger’s expertise is essential to this project.”

The researchers will perform experiments using cell lines provided by Dr. Chabot to explore the cellular processes that occur when the ratio between the short and long form of hnRNP A1 is disturbed. They will then validate their findings by examining ALS tissue samples generously donated to the Douglas-Bell Canada Brain Bank in Montréal and through other ALS labs in Canada.

Advancing ALS research

Insights from this project may also reveal hnRNPA1B as a target for the development of new therapies, such as a drug that could prevent or slow down its formation, and a biomarker to measure the effectiveness of a new drug designed to keep TDP-43 from moving out of the nucleus to the cytoplasm.

This research project is one of 8 research projects funded in 2018 by the ALS Canada Research Program, which is the only dedicated source of funding for ALS research in Canada. The funding of the project followed a rigorous scientific assessment by a panel of global ALS experts. The panelists evaluated a large pool of applications to identify projects that demonstrate 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