Sense-encoded poly-GR dipeptide repeat proteins correlate to neurodegeneration and uniquely co-localize with TDP-43 in dendrites of repeat expanded C9orf72 amyotrophic lateral sclerosis (P3.031)

Objective: Expanded repeats in the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and the related forontotemporal dementia (FTD). In the current study, we compared leading signature neuropathologic proteins. Background: Research on molecular and experimental models and neuropathology have identified many features including bidirectional transcription and translation into RNA foci and dipeptide repeat proteins (DPRs), and abnormal nuclear-cytoplasmic transport in neurons. The main hypothesized pathogenic mechanisms are C9orf72 haploinsufficiency and/or toxicity from one or more of bi-directionally transcribed repeat RNAs and their dipeptide repeat proteins (DPRs) poly-GP, poly-GA, poly-GR, poly-PR and poly-PA. Recently, nuclear import and/or export defects especially caused by arginine-containing poly-GR or poly-PR have been proposed as significant contributors to pathogenesis based on disease models. Design/Methods: We quantitatively studied and compared DPRs, nuclear pore proteins and normal C9orf72 protein in clinically-related and clinically-unrelated regions of the central nervous system, and compared them to phosphorylated TDP-43 (pTDP-43), the hallmark protein of ALS. Results: Of the five DPRs, only poly-GR was significantly abundant in clinically-related areas compared to unrelated areas (p Conclusions: Sense-encoded poly-GR DPR was unique and localized to neurites in the cytoplasm of neurons in motor regions of C9 ALS CNS. This is consistent with new emerging ideas about TDP-43 functions in dendrites. Study Supported by: ALS Association (5356S3), Target ALS (20134792), National Institute of Neurological Diseases and Stroke (NIH R01NS088578 and NS047101), and Pam Golden. Disclosure: Dr. saberi has nothing to disclose. Dr. Stauffer has nothing to disclose. Dr. Jiang has nothing to disclose. Dr. Garcia has nothing to disclose. Dr. schulte has nothing to disclose. Dr. Ohkubo has nothing to disclose. Dr. Schloffman has nothing to disclose. Dr. Maldonado has nothing to disclose. Dr. baughn has nothing to disclose. Dr. Rodriquez has nothing to disclose. Dr. Pizzo has nothing to disclose. Dr. Cleveland has nothing to disclose. Dr. Ravits has nothing to disclose.