Paschalis Kratsios, MD
Nidhi Sharma, PhD
Department of Neurobiology
In Collaboration with The Departments of Neurology and Chemistry
Dipeptide Repeat (DPR) Aggregation and Lysosomal Impairment in C9ORF72 ALS/FTD
Amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) are devastating, neurodegenerative diseases with no effective treatments. A hexanucleotide repeat expansion GGGGCC in the first intron of humanC9ORF72 is the most common genetic cause of ALS/FTD. The GGGGCC repeats are translated into dipeptide repeat proteins (DPRs )that are neurotoxic. We have demonstrated that the translation initiation factor eIF2D plays a significant role in DPRs synthesis in the C. elegans model of C9ORF72ALS/FTDALS. However, eIF2D does act partially; other regulatory factors likely act together with eIF2D as collaborators. The focus of my study is to investigate novel eIF2D collaborators in the DPRs synthesis using a biased and unbiased approach. In addition, I also aim to investigate altered lysosome function upon DPRs aggregation in C. elegans model of C9ORF72ALS/FTDALS using cutting-edge functional and quantitative imaging techniques.