Abstract 2381 The role of RPS25 in C9orf72-related amyotrophic lateral sclerosis

Amyotrophic Lateral Sclerosis (ALS), or Lou Gehrig's disease, is a neurodegenerative disease that affects motor neurons in the brain and the spinal cord. The mutation C9orf72 is involved in 30-50% of familial ALS. This mutation repeats the sequence GGGGCC in introns. In an unmutated gene, there are less than 30 of these repeats, but in a mutated gene, there are from 400 to thousands of these repeats. Although the C9orf72 mutation occurs within an intron, the mutation is expressed because the expanded sequence undergoes repeated non-AUG (RAN) translation. RAN translation of C9orf72 generates dipeptide repeat proteins (DPRs) which can accumulate in the central nervous system and lead to ALS through protein toxicity. Ribosomal Protein Subunit 25 (RPS25) plays a role in the synthesis of DPRs by regulating RAN translation. RPS25 is a non-essential eukaryotic protein component of the 40S ribosomal subunit which is found in the cytoplasm. RPS25 plays an important role in RAN translation of C9orf72. When the RPS25 gene is deleted, DPR levels decrease without impacting overall translation processes. This implies that inhibiting RPS25 can be a potential avenue for a therapeutic target for C9orf72-related ALS. RPS25 is also involved in internal ribosomal entry site (IRES) - mediated translation and ribosomal shunting. IRES-mediated translation initiates independently of cap structure recognition. Ribosome shunting is another mechanism for initiating translation. Unlike IRES-mediated translation, ribosomes are recruited to mRNA by a cap-dependent process. However, in ribosome shunting, large segments of the mRNA are bypassed before translation is initiated at an AUG start codon. In summary, RPS25 has been implicated in several noncanonical translation processes and therefore its structure and function within the ribosome is of key importance. Our SMART team, with the support from 3-D Molecular designs, has modeled RPS25 to view the structure of RPS25.