| Property | Value |
|---|---|
| Protein Name | C9orf72 protein |
| Gene | C9orf72 |
| UniProt ID | Q96LT7 |
| PDB ID | Predicted; cryo-EM structures in development |
| Molecular Weight | ~54 kDa |
| Subcellular Localization | Cytoplasm; associated with endosomes and lysosomes |
| Protein Family | DENN domain family |
C9orf72 protein is a protein. This page describes its structure, normal nervous system function, role in neurodegenerative disease, and potential as a therapeutic target.
The C9orf72 protein is a 481-amino acid protein with a DENN (Differential Expression in Normal and Neoplastic cells) domain[1]:
The DENN domain functions as a guanine nucleotide exchange factor (GEF) for Rab GTPases, particularly Rab8 and Rab39.
C9orf72 is essential for cellular trafficking:
The hexanucleotide repeat expansion causes disease through multiple mechanisms[2]:
The repeat expansion undergoes RAN translation producing five toxic DPRs:
C9orf72 expression data available from the Allen Brain Atlas:
The C9orf72 protein contains a differentially expressed in normal and neoplastic cells (DENN) domain, which functions as a guanine nucleotide exchange factor (GEF) for Rab GTPases[1:1]. This domain architecture suggests a role in regulating vesicular trafficking and autophagy[2:1]. The protein is expressed ubiquitously in the brain, with high levels in cerebellar granule cells, pyramidal neurons of the hippocampus, and cortical neurons[3].
The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is a GGGGCC hexanucleotide repeat expansion in the first intron of the C9orf72 gene[4]. This expansion leads to:
In Parkinson's disease, C9orf72 expansions have been associated with α-synuclein pathology and Lewy body formation[4:1]. The protein's role in autophagy regulation connects to the broader mechanisms of protein aggregate clearance that are impaired in both AD and PD[5].
Targeting C9orf72 for therapeutic intervention includes:
Murray, M.E.[4:2]: DeJesus-Hernandez, M. et al. Expanded GGGGCC hexanucleotide repeat. Neuron. 2011. ↩︎
Liu, X. et al. C9orf72 deficiency promotes motor deficits. Neurology. 2020. ↩︎ ↩︎ ↩︎
Webster, C.P. et al. The C9orf72 protein interacts with Rab1a. EMBO Reports. 2016. ↩︎