C9Orf72 Dipeptide Repeat Proteins plays an important role in the study of neurodegenerative diseases. This page provides comprehensive information about this topic, including its mechanisms, significance in disease processes, and therapeutic implications.
C9Orf72 Dipeptide Repeat Proteins is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
C9orf72 Dipeptide Repeat Proteins are toxic translation products of the hexanucleotide repeat expansion in the C9orf72 gene, the most common genetic cause of both Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD).
The C9orf72 gene contains a GGGGCC (G4C2) hexanucleotide repeat expansion in its first intron. This expansion can be hundreds to thousands of repeats in affected individuals, compared to <20 in healthy controls. The expansion leads to disease through three main mechanisms:
- Loss of C9orf72 function: Reduced protein expression
- RNA foci formation: Toxic RNA aggregates sequester RNA-binding proteins
- DPR translation: Non-canonical translation produces toxic dipeptide repeat proteins
The hexanucleotide repeat can be translated in all six reading frames, producing five different dipeptide repeats:
- Most abundant DPR in patient brains
- Forms neuronal intranuclear inclusions
- Impairs proteasome function
- Correlates with p62 pathology
- Detected in patient brain tissue
- Less aggregation-prone than GA
- Generated in all reading frames
- Most toxic DPR species
- Interacts with nucleolar proteins
- Causes nucleolar stress
- Impairs RNA processing
- Disrupts nuclear transport
- Highly toxic to neurons
- Disrupts nucleocytoplasmic transport
- Interacts with stress granules
- Impairs mitochondrial function
- Less abundant, less studied
- Contributes to aggregate formation
DPRs are repetitive proteins characterized by:
- Sequestration-prone sequences: Arginine-rich DPRs (GR, PR) are highly charged
- Aggregation-prone regions: GA repeats form β-sheet structures
- Post-translational modifications: Phosphorylation affects toxicity
- GR/PR DPRs disrupt nucleocytoplasmic transport
- Importin dysfunction
- Nuclear pore complex impairment
- Abnormal stress granule dynamics
- Sequestration of translation machinery
- Impaired stress response
- GA DPRs impair proteasome function
- Accumulation of ubiquitinated proteins
- Disrupted protein quality control
- DPRs localize to mitochondria
- Impaired mitochondrial dynamics
- Energy metabolism deficits
- Nucleolar stress from GR/PR
- Altered gene expression
- RNA processing defects
Current therapeutic approaches:
- ASO therapy: Targeting C9orf72 RNA to reduce DPR production (clinical trials)
- Small molecule inhibitors: Blocking non-canonical translation
- Protein aggregation modulators: Enhancing DPR clearance
- Neuroprotective agents: Targeting downstream toxicity pathways
- Mori K, et al. (2013). "The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS." Science 339(6125): 1335-1338.
- Zhang YJ, et al. (2014). "C9orf72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins." Nature Neuroscience 17(5): 682-693.
- Freibaum BD, et al. (2015). "GGGGCC repeat expansion in C9orf72 alters the nuclear transport of a group of proteins." Nature 525(7567): 129-133.
- Zhou Q, et al. (2017). "Structure of pathogenic aged proteins reveals a mechanism of aggregation." Nature 546(7658): 398-403.
C9Orf72 Dipeptide Repeat Proteins plays an important role in the study of neurodegenerative diseases. This page provides comprehensive information about this topic, including its mechanisms, significance in disease processes, and therapeutic implications.
- Renton AE, et al. (2011). "A hexanucleotide repeat expansion in C9orf72 is the cause of chromosome 9p21-linked ALS-FTD." Neuron 72(2): 257-268. DOI:10.1016/j.neuron.2011.09.010
- DeJesus-Hernandez M, et al. (2011). "Expanded GGGGCC hexanucleotide repeat in noncoding region of C9orf72 causes chromosome 9p-linked FTD and ALS." Neuron 72(2): 245-256. DOI:10.1016/j.neuron.2011.09.011
- Gendron TF, et al. (2013). "Antisense transcripts of the expanded C9orf72 hexanucleotide repeat form nuclear RNA foci and undergo repeat-associated non-ATG translation." Acta Neuropathologica 126(6):829-844. DOI:10.1007/s00401-013-1189-3
- Mori K, et al. (2013). "The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins that translate into aggregating dipeptide-repeat proteins in a translation." Science 339(6125): 1335-1338. DOI:10.1126/science.1232927
- Ash PE, et al. (2013). "Neurodegeneration. C9ORF72 repeat expansions cause neurodegeneration in Drosophila through toxic gain of function." Cell 152(4): 737-749. DOI:10.1016/j.cell.2013.01.006