Description
The nucleocytoplasmic mislocalization of the RNA editing enzyme ADAR2 in C9orf72 ALS/FTD
S. Moore1,2, A. Starr1, I Lorenzini1,E. Mendez1, J. Levy1, C. Burciu1, J Chew3, V. Belzil3, J. Robertson4, E. Alsop5, W. Xu6, J. Xu6, L. Petrucelli3, K. Jensen5, R. Sattler1
1Barrow Neurological Institute, AZ; 2Arizona State University, AZ, 3Department of Neuroscience, Mayo Clinic, FL; 4Toronto Western Hospital/Research Institute, Canada; 5Translational Genomics Research Institution, AZ, 6Shanghai Institute for Biological Science, China
The hexanucleotide repeat expansion GGGGCC (G4C2)n in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent findings indicate that dysfunction of nuclear-cytoplasmic transport of RNA binding proteins is disrupted in C9orf72 (C9). Similarly, we have identified that the RNA editing enzyme Adenosine Deaminase Acting on RNA 2 (ADAR2) is significantly mislocalized in C9orf72 repeat expansion mediated ALS. ADAR2 is responsible for adenosine (A) to Inosine (I) editing of double stranded RNA and its function has been shown to be essential for survival in ADAR2 knock out mice, which die shortly after birth. Additionally, altered ADAR2 function due to downregulation has been associated with sporadic forms of the disease. We provide evidence to suggest the mislocalization of ADAR2 in human induced pluripotent stem cell derived neurons (hiPSNs) of C9 patients, a C9 mouse model and C9 ALS post mortem tissue. To begin to understand the mislocalization specific to C9orf72 ALS, we have preliminary evidence that ADAR2 is mislocalized in the presence of the Arginine containing RAN translated dipeptides GR and PR. Surprisingly, we do not see any editing deficits at the GluA2 Q/R site in C9 cells and patient tissue. Current efforts are focused on discovering the overall impact of global A to I RNA editing deficits in C9 disease pathogenesis. Analysis of editing at over 400,000 known RNA editing sites indicates that there are vast RNA A to I editing deficits in C9orf72 mediated ALS, that are uniquely different from sporadic forms of the disease. Suggesting that the mislocalization of ADAR2 which predominantly occurs in C9orf72 mediated ALS might be responsible for the alteration of critical RNA processing events.