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Emerging Perspectives on Dipeptide Repeat Proteins in C9ORF72 ALS/FTD
Alexander Schmitz1,2, João Pinheiro Marques1,2,3, Irina Oertig1,2
1Department of Neurology, Center for Experimental Neurology, Inselspital University Hospital, Bern, Switzerland.
Frontiers in Cellular Neuroscience
|March 8, 2021
Summary
The C9orf72 gene mutation causes ALS and FTD through dipeptide repeat proteins (DPRs). This review details how specific DPRs contribute to neurodegeneration and discusses therapeutic strategies.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- 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 (C9ORF72) gene.
- This expansion leads to disease through C9ORF72 protein loss-of-function, RNA foci, and dipeptide repeat proteins (DPRs) produced by repeat-associated non-AUG (RAN) translation.
Purpose of the Study:
- To review current knowledge on the specific involvement of individual DPRs in C9ORF72-related ALS and FTD pathogenesis.
- To highlight recent advances in understanding DPRs' effects on disease development and RAN translation mechanisms.
Main Methods:
- Compilation of current neuropathological and cellular study findings.
- Review of recent literature on DPRs, RAN translation, and therapeutic options.
Main Results:
- Five DPRs (GA, GR, PA, PR, GP) are known, with varying contributions to disease pathology.
- Arginine-rich DPRs impact nucleolar protein quality control; poly-GR correlates with neurodegeneration.
- Recent findings shed light on RAN translation mechanisms, modulators, and potential therapeutic targets.
Conclusions:
- Individual DPRs play specific roles in C9ORF72-related neurodegenerative diseases.
- Understanding DPRs and RAN translation is crucial for developing effective therapeutic strategies for ALS and FTD.
