The <i>C9orf72</i> GGGGCC Repeat Is Translated into Aggregating Dipeptide-Repeat Proteins in FTLD/ALS

TLDR

We have content for each. Let's aggregate: Background: combine all background sentences: "Unusual Aggregates Several recent papers have revealed the unexpected genetic and pathological overlap between frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). The most common genetic cause is the GGGGCC hexanucleotide repeat expansion upstream of the C9orf72 coding region affecting about 10% of all patients. C9orf72 patients show two distinct types of ubiquitinated inclusions in the central nervous system, one of which was identified as phosphorylated TDP-43 protein. Let's craft: "Frontotemporal lobar degeneration and amyotrophic lateral sclerosis share a genetic and pathological overlap, with about 10% of patients carrying a GGGGCC hexanucleotide repeat expansion in C9orf72 that produces ubiquitinated inclusions, many of which lack TDP‑43 and whose disease‑causing protein remains unidentified." Purpose: "It is currently unknown how repeat expansion might lead to neurodegeneration." So sentence: "The study aims to determine how the C9orf72 repeat expansion contributes to neurodegeneration." Mechanism: The sentence from Mechanism, Findings: "discovered that most of these characteristic inclusions contain poly-(Gly-Ala) and, to a lesser extent, poly-(Gly-Pro) and poly-(Gly-Arg) dipeptide-repeat proteins that are generated by non-ATG–initiated translation from the expanded GGGGCC repeats in three reading frames." So mechanism: "The authors identified that the inclusions contain poly‑Gly‑Ala, poly‑Gly‑Pro, and poly‑Gly‑Arg dipeptide‑repeat proteins produced by non‑ATG‑initiated translation of the expanded GGGGCC repeats in three reading frames." Findings: "The findings yield mechanistic insight into the pathogenesis of FTLD/ALS with C9orf72 repeat expansions and directly link this common mutation to the characteristic pathology." So: "These findings provide mechanistic insight into FTLD/ALS pathogenesis by linking the C9orf72 repeat expansion to the characteristic dipeptide‑repeat protein inclusions." Other: "Mori et al." That's just a citation.

Abstract

Unusual Aggregates Several recent papers have revealed the unexpected genetic and pathological overlap between frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). The most common genetic cause is the GGGGCC hexanucleotide repeat expansion upstream of the C9orf72 coding region affecting about 10% of all patients. It is currently unknown how repeat expansion might lead to neurodegeneration. C9orf72 patients show two distinct types of ubiquitinated inclusions in the central nervous system, one of which was identified as phosphorylated TDP-43 protein. However, all inclusions in the cerebellum and most inclusions in the hippocampus and neocortex lack TDP-43, and the actual disease protein is unknown. Mori et al. (p. 1335 , published online 7 February; see the Perspective by Taylor ) discovered that most of these characteristic inclusions contain poly-(Gly-Ala) and, to a lesser extent, poly-(Gly-Pro) and poly-(Gly-Arg) dipeptide-repeat proteins that are generated by non-ATG–initiated translation from the expanded GGGGCC repeats in three reading frames. The findings yield mechanistic insight into the pathogenesis of FTLD/ALS with C9orf72 repeat expansions and directly link this common mutation to the characteristic pathology.