Emerging Perspectives on Dipeptide Repeat Proteins in C9ORF72 ALS/FTD
Open Access
- 18 February 2021
- journal article
- review article
- Published by Frontiers Media SA in Frontiers in Cellular Neuroscience
Abstract
The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is a hexanucleotide expansion in the chromosome 9 open reading frame 72 gene (C9ORF72). This hexanucleotide expansion consists of GGGGCC (G4C2) repeats that have been implicated to lead to three main modes of disease pathology: loss of function of the C9ORF72 protein, the generation of RNA foci, and the production of dipeptide repeat proteins (DPRs) through repeat-associated non-AUG (RAN) translation. Five different DPRs are currently known to be formed: glycine–alanine (GA) and glycine–arginine (GR) from the sense strand, proline–alanine (PA), and proline–arginine (PR) from the antisense strand, and glycine–proline (GP) from both strands. The exact contribution of each DPR to disease pathology is currently under intense scrutiny and is still poorly understood. However, recent advances in both neuropathological and cellular studies have provided us with clues enabling us to better understand the effect of individual DPRs on disease pathogenesis. In this review, we compile the current knowledge of specific DPR involvement on disease development and highlight recent advances, such as the impact of arginine-rich DPRs on nucleolar protein quality control, the correlation of poly-GR with neurodegeneration, and the possible involvement of chimeric DPR species. Further, we discuss recent findings regarding the mechanisms of RAN translation, its modulators, and other promising therapeutic options.Funding Information
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
This publication has 122 references indexed in Scilit:
- Antisense transcripts of the expanded C9ORF72 hexanucleotide repeat form nuclear RNA foci and undergo repeat-associated non-ATG translation in c9FTD/ALSActa Neuropathologica, 2013
- Modeling key pathological features of frontotemporal dementia with C9ORF72 repeat expansion in iPSC-derived human neuronsActa Neuropathologica, 2013
- Expanded GGGGCC repeat RNA associated with amyotrophic lateral sclerosis and frontotemporal dementia causes neurodegenerationProceedings of the National Academy of Sciences of the United States of America, 2013
- The product of C9orf72, a gene strongly implicated in neurodegeneration, is structurally related to DENN Rab-GEFsBioinformatics, 2013
- Clinico-pathological features in amyotrophic lateral sclerosis with expansions in C9ORF72Brain, 2012
- Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: clinical, neuroanatomical and neuropathological featuresBrain, 2012
- Clinical and neuropathologic heterogeneity of c9FTD/ALS associated with hexanucleotide repeat expansion in C9ORF72Acta Neuropathologica, 2011
- Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALSNeuron, 2011
- A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTDNeuron, 2011
- Non-ATG–initiated translation directed by microsatellite expansionsProceedings of the National Academy of Sciences of the United States of America, 2010