Translation of dipeptide repeat proteins from the C9ORF72 expanded repeat is associated with cellular stress

Yoshifumi Sonobe, Ghanashyam Ghadge, Katsuhisa Masaki, Ataman Sendoel, Elaine Fuchs, Raymond P. Roos

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Expansion of a hexanucleotide repeat (HRE), GGGGCC, in the C9ORF72 gene is recognized as the most common cause of familial amyotrophic lateral sclerosis (FALS), frontotemporal dementia (FTD) and ALS-FTD, as well as 5–10% of sporadic ALS. Despite the location of the HRE in the non-coding region (with respect to the main C9ORF72 gene product), dipeptide repeat proteins (DPRs) that are thought to be toxic are translated from the HRE in all three reading frames from both the sense and antisense transcript. Here, we identified a CUG that has a good Kozak consensus sequence as the translation initiation codon. Mutation of this CTG significantly suppressed polyglycine-alanine (GA) translation. GA was translated when the G4C2 construct was placed as the second cistron in a bicistronic construct. CRISPR/Cas9-induced knockout of a non-canonical translation initiation factor, eIF2A, impaired GA translation. Transfection of G4C2 constructs induced an integrated stress response (ISR), while triggering the ISR led to a continuation of translation of GA with a decline in conventional cap-dependent translation. These in vitro observations were confirmed in chick embryo neural cells. The findings suggest that DPRs translated from an HRE in C9ORF72 aggregate and lead to an ISR that then leads to continuing DPR production and aggregation, thereby creating a continuing pathogenic cycle.

Original languageEnglish
Pages (from-to)155-165
Number of pages11
JournalNeurobiology of Disease
Volume116
DOIs
Publication statusPublished - Aug 1 2018

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Dipeptides
Frontotemporal Dementia
Clustered Regularly Interspaced Short Palindromic Repeats
Genes
Reading Frames
Peptide Initiation Factors
Proteins
Initiator Codon
Poisons
Consensus Sequence
Chick Embryo
Alanine
Transfection
Mutation

All Science Journal Classification (ASJC) codes

  • Neurology

Cite this

Translation of dipeptide repeat proteins from the C9ORF72 expanded repeat is associated with cellular stress. / Sonobe, Yoshifumi; Ghadge, Ghanashyam; Masaki, Katsuhisa; Sendoel, Ataman; Fuchs, Elaine; Roos, Raymond P.

In: Neurobiology of Disease, Vol. 116, 01.08.2018, p. 155-165.

Research output: Contribution to journalArticle

Sonobe, Yoshifumi ; Ghadge, Ghanashyam ; Masaki, Katsuhisa ; Sendoel, Ataman ; Fuchs, Elaine ; Roos, Raymond P. / Translation of dipeptide repeat proteins from the C9ORF72 expanded repeat is associated with cellular stress. In: Neurobiology of Disease. 2018 ; Vol. 116. pp. 155-165.
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