$125,000 awarded to Dr. Janice Robertson, Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, in collaboration with Dr. Liang Zhang, University Health Network.
Mutations in the C9orf72 gene are the most common genetic cause of ALS. These mutations are unique in that unlike most other ALS-linked genes, where there is often a mistake in a single piece of DNA, C9orf72 mutations involve a section of DNA that is abnormally repeated hundreds or even thousands of times. These repeat mutations result in less of the normal C9orf72 protein being produced within cells, which may contribute to the disease process. Since this discovery researchers have sought to determine the biological function of C9orf72 in order to better understand how loss of this protein can contribute to disease.
Dr. Robertson and her team have previously used a powerful technique called single-nucleus RNA-sequencing (snRNA-seq) to investigate the biological pathways the C9orf72 protein may affect. In conjunction with additional studies in the lab, data showed that loss of C9orf72 is associated with the upregulation of another receptor protein, called GluA1. This means that when C9orf72 levels are reduced, the GluA1 receptor works overtime which can lead to activation of a cell death pathway called glutamate excitotoxicity, which is believed to be one of the targets for riluzole, the first approved therapy for ALS.
In this study, Dr. Robertson and her team propose to establish the relevance of these findings by investigating C9orf72 deficiency and its effects on a mouse model of ALS. This project will provide a better understanding of how the loss of C9orf72 can influence glutamate excitotoxicity in ALS, and potentially lead the way to identifying new treatment targets for the disease.