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

• DOI: 10.1126/science.1232927
• Publication Date: 2013-02-08T02:47:59Z
• Authors: Kohji Mori; Shih-Ming Weng; Thomas Arzberger; Stephanie May; Kristin Rentzsch; Elisabeth Kremmer; Bettina Schmid; Hans A. Kretzschmar; Marc Cruts; Christine Van Bro...; Christian Haass; Dieter Edbauer
• Keywords: Heterozygote; metabolism [Hippocampus]; Hippocampus; metabolism [Adaptor Proteins, Signal Transducing]; Open Reading Frames; 03 medical and health sciences; Cerebellum; Sequestosome-1 Protein; pathology [Cerebellum]; Humans; SQSTM1 protein, human; pathology [Amyotrophic Lateral Sclerosis]; Adaptor Proteins, Signal Transducing; 0303 health sciences; DNA Repeat Expansion; C9orf72 Protein; pathology [Frontotemporal Lobar Degeneration]; metabolism [Amyotrophic Lateral Sclerosis]; Amyotrophic Lateral Sclerosis; Proteins; metabolism [Proteins]; metabolism [Cerebellum]; genetics [Proteins]; 13; metabolism [Frontotemporal Lobar Degeneration]; 3. Good health; DNA-Binding Proteins; genetics [Amyotrophic Lateral Sclerosis]; pathology [Hippocampus]; Protein Biosynthesis; ddc:320; genetics [Frontotemporal Lobar Degeneration]; metabolism [DNA-Binding Proteins]; C9orf72 protein, human; Frontotemporal Lobar Degeneration

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.