C9orf72 Dipeptide Repeat Proteins (DPRs) are toxic protein aggregates generated by the hexanucleotide repeat expansion (GGGGCC) in the C9orf72 gene, the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)[1]. The repeat expansion leads to the production of five different dipeptide repeat proteins through a non-ATG (RAN) translation mechanism: poly-GA, poly-GR, poly-PR, poly-PA, and poly-GP[2]. These DPRs form insoluble inclusions in the brains and spinal cords of patients, contributing to neurodegeneration through multiple molecular mechanisms.
The GGGGCC repeat expansion in the first intron of C9orf72 undergoes bidirectional transcription, producing both sense and antisense RNA transcripts that form nuclear RNA foci[3]. These expanded RNA repeats are translated in all three reading frames without a start codon, a process called Repeat-Associated Non-ATG (RAN) translation, generating the five DPR species[4]. RAN translation occurs in both the forward (sense) and reverse (antisense) directions, producing poly-GA (glycine-alanine), poly-GR (glycine-arginine), poly-PR (proline-arginine), poly-PA (proline-alanine), and poly-GP (glycine-proline) proteins.
The different DPR species exhibit distinct toxicities:
C9orf72-associated ALS accounts for approximately 40% of familial ALS cases and 5-10% of sporadic ALS[8]. The DPRs contribute to motor neuron death through:
C9orf72 expansions are the most common cause of familial FTD, particularly the behavioral variant (bvFTD)[10]. DPR pathology is widespread in the frontal and temporal cortices, correlating with clinical symptoms.
Many patients present with overlapping ALS-FTD syndromes, reflecting the shared pathophysiology of both diseases[11]. The clinical phenotype depends on the distribution of pathology—motor cortex involvement leads to ALS, while frontal/temporal involvement produces FTD.
Multiple ASO therapies are in development to suppress C9orf72 repeat RNA expression[12]. These ASOs target either the repeat RNA itself or the sense/antisense transcripts to reduce DPR production.
Research efforts focus on developing RAN translation inhibitors and compounds that prevent DPR aggregation[13].
CRISPR-based approaches to specifically edit or silence the expanded allele are under investigation[14].
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