Feb 9, 2013

The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS

Science
Kohji MoriDieter Edbauer

Abstract

Expansion of a GGGGCC hexanucleotide repeat upstream of the C9orf72 coding region is the most common cause of familial frontotemporal lobar degeneration and amyotrophic lateral sclerosis (FTLD/ALS), but the pathomechanisms involved are unknown. As in other FTLD/ALS variants, characteristic intracellular inclusions of misfolded proteins define C9orf72 pathology, but the core proteins of the majority of inclusions are still unknown. Here, we found 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 presumably generated by non-ATG-initiated translation from the expanded GGGGCC repeat in three reading frames. These findings directly link the FTLD/ALS-associated genetic mutation to the predominant pathology in patients with C9orf72 hexanucleotide expansion.

Mentioned in this Paper

C9orf72 protein, human
Abnormal Degeneration
Protoplasm
Gene Products, Protein
Amyotrophic Lateral Sclerosis
Protein Biosynthesis
Reading Frames (Nucleotide Sequence)
Amyotrophic Lateral Sclerosis, Guam Form
Unassigned Reading Frames
C9orf72 gene

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