TY  - GEN
T1  - The conserved multi-functional nuclear protein dss-1/Sem1 is required for C9orf72-associated ALS/FTD dipeptide toxicity
AU  - Puleo, Noah
AU  - Lamitina, Todd
DO  - 10.17912/micropub.biology.000262
UR  - http://beta.micropublication.org/journals/biology/micropub-biology-000262/
AB  - Neurodegenerative diseases caused by short expansive repeats like the (CAG) in Huntington’s disease (Orr 2012) or the (GGGGCC) repeat in C9orf72-associated Amyotrophic lateral sclerosis (ALS)/Frontotemporal dementia (FTD) (DeJesus-Hernandez et al. 2011) undergo an unusual type of translation called repeat associated non-AUG-dependent (RAN) translation (Cleary and Ranum 2014). Interestingly, RAN translation occurs without an AUG start codon (Cleary and Ranum 2014). This allows for the (GGGGCC) repeat mutation to be translated, even though it is located in the intron between exon 1 and exon 2 of the C9orf72 gene, which would normally be spliced out and degraded (DeJesus-Hernandez et al. 2011). Translation of the repeat occurs in all 3 reading frames, leading to the production of three distinct dipeptide repeat proteins (DPRs). RAN translation begins within the (GGGGCC) repeat, but the exact translation initiation site remains unclear. However, RAN translation does not stop at the end of the repeat and will continue to translate the intronic sequence until it reaches a stop codon. This means that each of the distinct DPRs will be fused to peptides encoded in the downstream intron sequence. Because the DPRs are derived from intron sequence that is spliced out of the mature C9orf72 mRNA, none of these intron-derived DPR fusion peptides are incorporated into the ‘normal’ C9orf72 protein. While it is known that the DPR fusion peptides are made in patients, the precise sequences of the DPR fusion peptides that they produce is not currently known. Therefore, questions about where precisely RAN translation initiates, how many repeats are produced, and whether the number of repeats produced are uniform or heterogenous remain important but unresolved questions.
PY  - 2020
JO  - microPublication Biology
ER  -