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Home›Poly-lateral›Translation of the poly (GR) framework in C9ORF72-ALS / FTD is regulated by the cis elements involved in alternative splicing

Translation of the poly (GR) framework in C9ORF72-ALS / FTD is regulated by the cis elements involved in alternative splicing

By Allen Rodriquez
June 22, 2021
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This article was originally published here

Aging Neurobiol. May 8, 2021; 105: 327-332. doi: 10.1016 / j.neurobiolaging.2021.04.030. Online ahead of print.

ABSTRACT

GGGGCC (G4VS2) repeated expansion into the first intron of C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia, two devastating age-related neurodegenerative disorders. The sense and antisense repeats can be translated into 5 different dipeptide repeats, such as poly (GR), which is toxic in various cell and animal models. However, it is still unclear how poly (GR) is synthesized in patient neurons. Using a reporter construct containing 70 G4VS2 repeats flanked by human intron and exon sequences, we show that translation of the poly (GR) frame does not depend on repeats or the CUG initiation codon in the poly (GA) frame, suggesting that poly (GR) is not produced after shifting the ribosomal frame into the poly (GA) frame. However, deletion analysis suggests that translation of the poly (GR) frame depends on the length of the 5 ‘intronic sequence adjacent to G4VS2 say again. In addition, several 5´ cis elements that should be involved in alternative splicing regulate poly (GR) synthesis. These results suggest that translation of RNAs repeated in the poly (GR) frame is regulated by multiple cis elements, possibly by RNA secondary structures and / or associated RNA binding proteins.

PMID:34157654 | DO I:10.1016 / j.neurobiolaging.2021.04.030



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