Investigating the templated propagation and impact of pathogenic FUS in hiPSCs-derived cerebral organoids

The buildup of abnormal protein aggregates is a hallmark of ALS cases, possibly contributing to disease progression. One key protein involved in some cases of ALS is Fused in Sarcoma (FUS), believed to contribute to normal cell function by playing a role in the complex biology between RNA and proteins. Pathogenic variants (mutations) in the FUS gene cause the protein to change its shape, favoring the formation of aggregates inside cells.

While researchers are still trying to understand how ALS starts, one hypothesis is that potentially toxic protein aggregates spread from cell to cell, contributing to disease progression. In this study, Dr. Rouleau and his team will test if cells from people living with FUS-ALS can induce the spread of FUS protein aggregates in organoid models. Cerebral organoids are small, three-dimensional brain-like structures. These 3D models are thought, by some, to be a good model to study disease processes and progression because they might better replicate the real environment in which cells are found in our body compared to 2D models.

Dr. Rouleau also aims to understand the role of tiny cellular compartments called extracellular vesicles and cell connections called tunneling nanotubes in this spread. Additionally, they will investigate if these propagated FUS aggregates affect the recipient cell’s ability to properly translate RNA into proteins. Their research aims to provide a better understanding of FUS pathology, providing valuable insights into the onset and progression of ALS.

Collaborators: Drs. Patrick Dion & Chantelle Sephton

Dr. Rouleau, with ALS Canada as a contributor, has played a significant role in advancing genetic discoveries in ALS. The study that first identified the SOD1 gene variant as a risk factor for ALS included work by Dr. Rouleau. ALS Canada helped to support that initial SOD1 study and since then, our funding has played an important role in the global understanding of SOD1 biology and several other ALS genes, such as FUS.