Affinage

C9ORF72

Guanine nucleotide exchange factor C9orf72 · UniProt Q96LT7

Length
481 aa
Mass
54.3 kDa
Annotated
2026-04-28
100 papers in source corpus 28 papers cited in narrative 27 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

C9ORF72 is a DENN-domain protein that functions as a GDP/GTP exchange factor for Rab GTPases (Rab8a, Rab39b) within a trimeric complex with SMCR8 and WDR41, serving as a central regulator of autophagy initiation, endolysosomal trafficking, mTORC1 signaling, and synaptic vesicle homeostasis (PMID:27617292, PMID:27494456, PMID:27334615, PMID:35876881). Through its DENN domain, C9ORF72 recruits the ULK1 autophagy initiation complex and interacts with Rag GTPases to coordinate lysosomal biogenesis and mTORC1 nutrient sensing; loss of C9ORF72 impairs autolysosomal degradation, causing aberrant STING-driven type I interferon responses in myeloid cells and enhanced synaptic pruning by microglia (PMID:30669939, PMID:32100453, PMID:32814898, PMID:34133945). C9ORF72 also localizes to mitochondria where it stabilizes the complex I assembly factor TIMMDC1 via the prohibitin complex, and to the nucleus where it promotes NHEJ-mediated DNA damage repair (PMID:33545050, PMID:36220889). A GGGGCC hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia, operating through haploinsufficiency of C9ORF72 protein functions combined with toxic gain-of-function from nuclear RNA foci that disrupt nucleocytoplasmic transport and nuclear speckle integrity, and from RAN-translated dipeptide repeat proteins that impair heterochromatin, sequester TDP-43 and VCP, and activate p53-dependent neurodegeneration (PMID:21944778, PMID:26308891, PMID:30765536, PMID:33482083, PMID:39181135).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 2011 High

    Identification of the GGGGCC repeat expansion in C9ORF72 as the genetic cause of chromosome 9p-linked ALS/FTD established the gene's disease relevance and immediately revealed dual pathomechanisms — loss of a transcript isoform (haploinsufficiency) and nuclear RNA foci (toxic gain-of-function).

    Evidence Genetic linkage in ALS/FTD families, transcript analysis showing loss of one isoform, RNA FISH detecting nuclear foci in patient tissue; two independent simultaneous publications

    PMID:21944778 PMID:21944779

    Open questions at the time
    • Normal cellular function of C9ORF72 protein was unknown
    • Mechanism by which RNA foci cause toxicity was uncharacterized
    • Whether repeat-associated non-ATG translation occurs was untested
  2. 2013 Medium

    Computational detection of DENN-domain homology in C9ORF72 predicted it functions as a Rab GEF in membrane trafficking, providing the first framework for understanding its normal cellular role.

    Evidence Sensitive sequence/structure homology searches (bioinformatics)

    PMID:23329412

    Open questions at the time
    • No experimental validation of GEF activity
    • Specific Rab substrates were unidentified
    • Prediction based on remote homology only
  3. 2015 High

    Demonstration that HRE RNA physically interacts with RanGAP1 and disrupts nucleocytoplasmic transport in patient neurons and Drosophila established the first mechanistic gain-of-function pathway downstream of the repeat expansion.

    Evidence Candidate genetic screen in Drosophila, Co-IP/pulldown of RanGAP1 with HRE RNA, nuclear import assays in iPSC neurons, pharmacological and ASO rescue

    PMID:26308891

    Open questions at the time
    • Relative contribution of RNA foci versus DPR proteins to nucleocytoplasmic transport defects was unclear
    • Whether nucleocytoplasmic transport disruption is sufficient for neurodegeneration was unknown
  4. 2016 High

    Biochemical demonstration that C9ORF72 forms a stable complex with SMCR8 and WDR41 and acts as a GEF for Rab8a and Rab39b, while also interacting with the ULK1 complex to regulate autophagy initiation, established the core molecular function of the C9ORF72 protein.

    Evidence In vitro GEF assays, reciprocal Co-IP of SMCR8/WDR41/C9ORF72 complex, autophagy flux assays in cell lines, primary neurons, and patient iNeurons, Smcr8 KO mouse phenotyping

    PMID:27334615 PMID:27494456 PMID:27617292

    Open questions at the time
    • Structural basis of complex assembly and GEF catalysis was unresolved
    • Full spectrum of Rab substrates was not defined
    • How autophagy deficiency leads specifically to neurodegeneration was unclear
  5. 2017 High

    Linking C9ORF72 to RAB7L1-dependent vesicle trafficking and trans-Golgi network integrity in patient motor neurons demonstrated that haploinsufficiency impairs specific endomembrane pathways beyond autophagy.

    Evidence Endogenous Co-IP of C9ORF72-RAB7L1, vesicle trafficking assays, trans-Golgi morphology in patient iPSC motor neurons and fibroblasts, ASO rescue

    PMID:28334866

    Open questions at the time
    • Relative importance of Golgi versus endolysosomal defects in disease pathogenesis was unresolved
    • Whether RAB7L1 is a direct GEF substrate was not established
  6. 2018 High

    Studies in iPSC motor neurons and knockout mice revealed that C9ORF72 haploinsufficiency impairs endosomal trafficking and lysosomal biogenesis, leading to glutamate receptor accumulation and excitotoxicity — connecting vesicle trafficking defects to a neuron-specific vulnerability mechanism.

    Evidence iPSC-derived motor neurons, endosomal Co-IP, lysosomal biogenesis assays, constitutively active RAB5 rescue, C9orf72 KO mice

    PMID:29400714

    Open questions at the time
    • Whether excitotoxicity is the primary driver of motor neuron death in patients was untested
    • Contribution of glial C9ORF72 loss to the phenotype was not addressed
  7. 2018 High

    Proteomic and genetic analysis of the SMCR8-C9ORF72 complex demonstrated mutual protein stabilization and a shared role in suppressing lysosomal exocytosis and autoimmunity, extending C9ORF72 function to immune regulation.

    Evidence Quantitative mass spectrometry, Smcr8 KO mice, LAMP1 surface staining and lysosomal exocytosis assays in macrophages

    PMID:29950492

    Open questions at the time
    • How lysosomal exocytosis defects drive autoimmunity at the molecular level was incompletely understood
    • Whether immune phenotypes contribute to neurodegeneration in patients was unknown
  8. 2019 High

    Poly(PR) DPR was shown to bind DNA, disrupt HP1α liquid-phase separation at heterochromatin, alter histone methylation, and induce repetitive element derepression, establishing a chromatin-level toxic gain-of-function mechanism distinct from nucleocytoplasmic transport disruption.

    Evidence Mouse model expressing GFP-(PR)50, ChIP, HP1α LLPS assays, histone methylation analysis, RNA-seq, behavioral testing

    PMID:30765536

    Open questions at the time
    • Whether heterochromatin disruption occurs in human patient neurons was not demonstrated
    • Relative contribution of chromatin versus other poly-PR toxicity pathways was undefined
  9. 2019 High

    Discovery that C9ORF72 loss impairs STING degradation through the autolysosomal pathway, causing selective type I interferon hyperactivation, provided a molecular mechanism linking C9ORF72 endolysosomal function to neuroinflammation.

    Evidence Myeloid-specific conditional KO mice, STING degradation assays, type I IFN measurement, STING inhibitor rescue, patient macrophage validation

    PMID:32814898

    Open questions at the time
    • Whether STING-driven inflammation is therapeutically targetable in patients was untested
    • Contribution of STING pathway to motor neuron-autonomous degeneration was unclear
  10. 2019 High

    Mapping the direct C9ORF72–ATG13 interaction to the DENN domain and demonstrating that only the long isoform rescues autophagy and dendritic morphology in KO neurons resolved the isoform-specific functional requirement for autophagy regulation.

    Evidence C9orf72 KO hippocampal neuron culture, Co-IP with domain mapping, LC3-II puncta assay, dendritic morphology rescue with long isoform

    PMID:30669939

    Open questions at the time
    • Whether short isoform has an independent function was not resolved
    • Structural detail of the DENN–ATG13 interface was lacking
  11. 2020 Medium

    Connecting C9ORF72 to Rag GTPase regulation and mTORC1 signaling provided a mechanistic explanation for the lysosome accumulation and TFEB nuclear translocation observed in C9ORF72-deficient cells, unifying autophagy and lysosomal phenotypes under a nutrient sensing framework.

    Evidence Co-IP and DENN domain mapping of Rag interaction, mTORC1 activity assays, TFEB/MITF/TFE3 nuclear translocation, active Rag rescue

    PMID:32100453

    Open questions at the time
    • Whether C9ORF72 acts as a GEF for Rag GTPases or merely a scaffold was not resolved
    • Relationship between mTORC1 and STING degradation defects was not integrated
  12. 2020 High

    Demonstration that poly(GR) directly sequesters TDP-43 into cytoplasmic inclusions, independent of RNA, and that nucleocytoplasmic transport factor mislocalization facilitates this process, linked two hallmark ALS/FTD pathologies — DPR and TDP-43 aggregation — in a mechanistic cascade.

    Evidence Co-IP of poly(GR) with TDP-43, GFP-(GR)200 mouse model, nucleocytoplasmic transport factor imaging, ASO rescue reducing both poly(GR) and TDP-43 pathology in vivo

    PMID:32878979

    Open questions at the time
    • Whether TDP-43 sequestration is the primary downstream effector of neurotoxicity was not established
    • How poly(GR) selectivity for TDP-43 versus other nuclear proteins is determined was unknown
  13. 2020 High

    Identification of PKR as an activator of RAN translation from G4C2 repeats, with pharmacological inhibition (metformin) reducing DPR production and improving phenotypes in BAC mice, revealed a druggable regulator of toxic DPR biogenesis.

    Evidence Cell-based RAN translation assays, PKR-KO cells, dominant-negative PKR, C9orf72 BAC mouse model, metformin treatment, behavioral rescue

    PMID:32690681

    Open questions at the time
    • Clinical translatability of PKR inhibition or metformin was untested
    • Whether PKR activation is specific to C9ORF72 repeats or general to structured repeat RNAs was unclear
  14. 2021 High

    Discovery that C9ORF72 localizes to the mitochondrial intermembrane space via the AIFM1/CHCHD4 import pathway and stabilizes complex I assembly factor TIMMDC1 by recruiting the prohibitin complex revealed an entirely new compartment-specific function for C9ORF72 beyond membrane trafficking.

    Evidence Mitochondrial fractionation, import assay, Co-IP with TIMMDC1 and prohibitin, m-AAA protease degradation assay, complex I activity in patient neurons

    PMID:33545050

    Open questions at the time
    • Whether mitochondrial dysfunction is a primary driver of neurodegeneration or secondary was unresolved
    • How mitochondrial and autophagic functions of C9ORF72 are coordinated was unknown
  15. 2021 High

    Identification of p53 as the master transcriptional mediator of poly(PR/GR)-induced neurodegeneration, with p53 ablation completely rescuing neuronal death in mouse and fly models and patient iPSC neurons, established a convergent cell death pathway downstream of DPR toxicity.

    Evidence ATAC-seq, p53 conditional KO mice, C9orf72 mouse model survival, patient iPSC motor neuron rescue, Drosophila model

    PMID:33482083

    Open questions at the time
    • Whether p53 activation is direct (DPR-DNA damage) or indirect was not fully resolved
    • Therapeutic targeting of p53 in neurodegeneration poses oncogenic risk concerns
  16. 2021 High

    Showing that spliced circular intron RNA — not pre-mRNA — is the template for cytoplasmic DPR translation, exported via NXF1-NXT1, resolved a long-standing question about the identity and export mechanism of the RAN translation substrate.

    Evidence Single-molecule imaging, circular RNA characterization, lariat debranching assays, NXF1-NXT1 knockdown reducing DPR production

    PMID:34389711

    Open questions at the time
    • Whether blocking circular intron export is therapeutically viable was untested
    • Relative contribution of nuclear versus cytoplasmic DPR production was not quantified
  17. 2021 High

    Single-cell transcriptomics in C9orf72-deficient mice revealed that microglial inflammatory polarization with a type I IFN signature drives age-dependent excessive synaptic pruning and cognitive impairment, connecting C9ORF72 immune function to synaptic loss.

    Evidence C9orf72-deficient mice, single-cell transcriptomics, synaptic pruning assays, behavioral tests, amyloid mouse model cross

    PMID:34133945

    Open questions at the time
    • Whether microglial-mediated synapse loss is reversible was unknown
    • Human microglial phenotypes in C9ORF72 ALS/FTD were not directly profiled
  18. 2022 High

    Identification of synapsin as a direct C9ORF72 interactor via its longin domain, with C9ORF72 loss depleting synaptic vesicles and impairing excitatory neurotransmission, provided a molecular basis for the synaptic dysfunction observed in ALS/FTD patients.

    Evidence Endogenous Co-IP with domain mapping, C9orf72 KO mice, electrophysiology, electron microscopy of synaptic vesicles, patient tissue neuropathology

    PMID:35876881

    Open questions at the time
    • Whether synapsin reduction is a primary or secondary consequence of vesicle trafficking defects was unclear
    • Therapeutic rescue of synaptic vesicle pools was not attempted
  19. 2022 Medium

    Discovery that C9ORF72 is recruited to DNA damage sites and promotes NHEJ through DNA-PK complex assembly added a nuclear function, and showed that combined C9ORF72 loss and poly-GR expression causes synergistic DNA damage and PARP-1-dependent neuronal death.

    Evidence Live imaging of GFP-C9ORF72 at damage sites, NHEJ repair assay, DNA-PK Co-IP, KO mouse models, PARP-1 inhibitor rescue

    PMID:36220889

    Open questions at the time
    • Independent replication of the DNA repair function is needed
    • Whether DNA damage accumulation is a major contributor to human disease progression was not established
    • Structural basis of C9ORF72 interaction with DNA-PK complex was undefined
  20. 2024 High

    Demonstration that G4C2 repeat RNA disrupts nuclear speckle phase separation and that poly-GR sequesters SRRM2 to cause global splicing dysregulation revealed a new gain-of-function mechanism impacting RNA processing at the transcriptome-wide level.

    Evidence RNA FISH with nuclear speckle immunostaining, SRRM2 Co-IP with poly-GR, mouse model and patient postmortem tissue, iPSC neuron RNA-seq splicing analysis

    PMID:39181135

    Open questions at the time
    • Whether splicing disruption is an early or late event in disease progression was unknown
    • Specific splicing events most critical for neuronal survival were not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • A unified quantitative framework integrating the relative contributions of haploinsufficiency (autophagy, lysosome, mitochondria, synapse, DNA repair) versus gain-of-function toxicities (RNA foci, DPR proteins, splicing disruption, TDP-43 aggregation, p53 activation) to disease onset and progression in different cell types remains to be established.
  • No high-resolution structure of the C9ORF72–SMCR8–WDR41 complex with Rab substrates in a catalytic state
  • Cell-type-specific hierarchy of loss-of-function versus gain-of-function mechanisms is undefined
  • Whether therapeutic targeting of a single pathway (e.g., p53, STING, PKR, or ASO) is sufficient for clinical benefit is untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003924 GTPase activity 3 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005764 lysosome 3 GO:0005829 cytosol 3 GO:0005634 nucleus 2 GO:0005739 mitochondrion 1 GO:0005768 endosome 1
Pathway
R-HSA-1643685 Disease 5 R-HSA-9612973 Autophagy 5 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-112316 Neuronal System 2 R-HSA-162582 Signal Transduction 2 R-HSA-168256 Immune System 2 R-HSA-73894 DNA Repair 1
Partners
ATG13RAB39BRAB7L1RAB8ASMCR8SYN1TIMMDC1WDR41
Complex memberships
C9ORF72–SMCR8–WDR41ULK1 autophagy initiation complex

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 GGGGCC hexanucleotide repeat expansion in the noncoding region of C9ORF72 causes loss of one alternatively spliced C9ORF72 transcript and leads to formation of nuclear RNA foci, indicating dual loss-of-function and gain-of-function disease mechanisms. Genetic linkage analysis, transcript analysis, RNA FISH for nuclear foci in patient tissue Neuron High 21944778 21944779
2013 C9ORF72 protein is structurally related to DENN-domain Rab-GEF proteins by sensitive homology searches, predicting a role in membrane trafficking via Rab GTPase regulation. Computational homology/structure prediction (bioinformatics) Bioinformatics Medium 23329412
2015 The C9orf72 repeat expansion disrupts nucleocytoplasmic transport: RanGAP1 physically interacts with HRE RNA and is mislocalized in patient iPSC-derived neurons and brain tissue; nuclear import is impaired in HRE-expressing flies and iPSC neurons, and is rescued by small molecules and ASOs targeting G-quadruplexes. Candidate-based genetic screen in Drosophila, Co-IP/pulldown of RanGAP1 with HRE RNA, nuclear import assays in iPSC-derived neurons and patient brain tissue, pharmacological rescue Nature High 26308891
2016 C9orf72 interacts with Rab1a and the ULK1 autophagy initiation complex; acting as a Rab1a effector, C9orf72 controls initiation of autophagy by regulating Rab1a-dependent trafficking of the ULK1 complex to the phagophore. C9orf72 knockdown in cell lines and primary neurons attenuates autophagy and causes accumulation of p62-positive puncta. Co-IP, proximity ligation assay, autophagy flux assays in cell lines, primary neurons, and patient iNeurons; knockdown phenotyping The EMBO Journal High 27334615
2016 C9ORF72 forms a multiprotein complex with SMCR8, WDR41, and ATG101; this complex displays GTPase activity and acts as a GDP-GTP exchange factor (GEF) for RAB39B. SMCR8/C9ORF72 interacts with the ULK1 complex and regulates ULK1 expression and activity to control autophagy initiation; C9orf72 knockdown cells show impaired autophagy induction. Co-IP, in vitro GTPase/GEF assay, Smcr8 knockout mouse, autophagy flux assays, ULK1 activity measurements Science Advances High 27617292
2016 C9ORF72 acts as a GDP/GTP exchange factor for Rab8a and Rab39b as part of a stable complex with SMCR8 and WDR41; loss of C9orf72 expression causes autophagy dysfunction with p62/SQSTM1 aggregate accumulation in neuronal cultures. GEF biochemical assay, Co-IP, knockdown in neuronal cultures with p62 immunostaining Small GTPases Medium 27494456
2017 C9ORF72 interacts with RAB7L1 GTPase to regulate vesicle trafficking; C9orf72 haploinsufficiency leads to defective intracellular and extracellular vesicle trafficking and a dysfunctional trans-Golgi network phenotype in patient fibroblasts and iPSC-derived motor neurons. Restoring C9orf72 or targeting the HRE with ASOs rescued these defects. Co-IP of endogenous proteins, vesicle trafficking assays, trans-Golgi network morphology, ASO rescue in patient iPSC motor neurons and fibroblasts Brain High 28334866
2018 C9ORF72 interacts with endosomes and is required for normal vesicle trafficking and lysosomal biogenesis in motor neurons; C9orf72 haploinsufficiency triggers neurodegeneration through accumulation of glutamate receptors (excitotoxicity) and impaired clearance of dipeptide repeat proteins. Restoring C9orf72 or activating RAB5 rescued patient neuron survival. Human iPSC-derived motor neurons (iMNs), Co-IP with endosomal markers, vesicle trafficking assays, lysosomal biogenesis assays, RAB5 constitutively-active rescue, pharmacological rescue Nature Medicine High 29400714
2018 C9orf72 is essential for neurodevelopment and motility: loss of C9orf72 in zebrafish impairs axonogenesis and motility, upregulates Cyclin G1 (ccng1) and tp53; dominant-negative Cyclin G1 rescued all defects. The complete DENN domain is required for GTPase activity of C9orf72. Zebrafish morpholino knockdown, dominant-negative constructs, GTPase activity assay, genetic epistasis (tp53 and ccng1 knockdown rescue) Experimental Neurology Medium 29522758
2018 The C9orf72 long isoform complexes with SMCR8 (stabilizing it) and enables interaction with WDR41 in motor neurons; C9orf72 and SMCR8 have interdependent functions in suppressing autoimmunity and negatively regulating lysosomal exocytosis, as shown by elevated LAMP1 surface expression and enhanced lysosomal component secretion in Smcr8 and C9orf72 loss-of-function macrophages. Quantitative mass spectrometry proteomics, Co-IP, Smcr8 knockout mice, LAMP1 surface staining, lysosomal exocytosis assays in macrophages Genes & Development High 29950492
2019 C9orf72 is localized to both pre- and post-synaptic compartments; in C9orf72 knockout mice, post-synaptic SMCR8 is completely lost, Rab39b is downregulated, and GluR1 (AMPA receptor subunit) is significantly upregulated in the post-synaptic density of dorsal hippocampus, implicating C9orf72 in regulation of post-synaptic receptor levels. Synaptosomal and post-synaptic density fractionation, immunoprecipitation, C9orf72 KO mice, immunofluorescence with knockout-confirmed antibody Acta Neuropathologica Communications Medium 31651360
2019 C9orf72 is required for dendritic arborization and spine density in hippocampal neurons via promotion of autophagy; C9orf72 directly interacts with ATG13 of the ULK1-RB1CC1-ATG13-ATG101 autophagy initiation complex through its isoform-specific C-terminal DENN/dDENN domain. Loss of C9orf72 impairs basal autophagy and reduces ULK1 levels; rescue requires the long isoform that interacts with ULK1 complex. C9orf72 KO mouse hippocampal neuron culture, quantitative proteomics, Co-IP, domain mapping, LC3-II puncta assay, dendritic morphology imaging Autophagy High 30669939
2019 Poly(PR) dipeptide repeat protein binds DNA, localizes to heterochromatin, disrupts HP1α liquid-phase properties, decreases HP1α expression, causes abnormal histone methylation, nuclear lamina invaginations, repetitive element expression, and double-stranded RNA accumulation, leading to progressive neurodegeneration in mice. Mouse model expressing GFP-(PR)50, chromatin immunoprecipitation, immunofluorescence, HP1α LLPS assays, histone methylation analysis, RNA-seq, behavioral testing Science High 30765536
2019 C9orf72 loss-of-function in myeloid cells impairs STING degradation through the autolysosomal pathway, causing selective hyperresponsiveness to STING activators and elevated type I interferon response; blocking STING suppresses hyperactive interferon in C9orf72-/- cells and reduces splenomegaly/inflammation in mice. Conditional KO mice (myeloid-specific), dendritic cell isolation, STING degradation assays, type I IFN measurement, STING inhibitor treatment, patient blood/brain macrophage analysis Nature High 32814898
2019 C9orf72 loss promotes microglial transition to an inflammatory state with enhanced type I IFN signature, leading to age-dependent enhanced cortical synaptic pruning, altered learning and memory, and exacerbated synapse loss in amyloid accumulation mouse models. C9orf72-deficient mice, single-cell transcriptomics, synaptic pruning assays, behavioral tests, amyloid mouse model cross Neuron High 34133945
2020 C9orf72 associates with inactive (GDP-loaded) Rag GTPases via its DENN domain, affecting Rag/raptor/mTOR complex function and mTORC1 activity; C9orf72 loss leads to accumulation of lysosomes and autophagosomes with suppressed mTORC1 and enhanced nuclear translocation of MITF/TFE3/TFEB transcription factors. Active Rag GTPases rescue impaired mTORC1 localization and activity in C9orf72-deficient cells. Co-IP, domain mapping (DENN domain), lysosome/autophagosome morphology, mTORC1 activity assay, TFEB/MITF/TFE3 nuclear translocation, active/inactive Rag GTPase rescue Aging Cell Medium 32100453
2020 C9orf72 poly(GR) sequesters full-length TDP-43 in an RNA-independent manner, promoting cytoplasmic TDP-43 inclusion formation; poly(GR) also causes mislocalization of nucleocytoplasmic transport factors and nuclear pore complex proteins, which leads to aberrant cytoplasmic TDP-43 accumulation and co-aggregation with poly(GR). ASOs targeting G4C2 repeats reduced poly(GR) and TDP-43 pathology in vivo. Co-immunoprecipitation, cell-based TDP-43 aggregation assay, GFP-(GR)200 mouse model, immunofluorescence, ASO treatment in mice with neurofilament light measurement Science Translational Medicine High 32878979
2019 C9orf72-containing complex (with SMCR8) in macrophages regulates lysosomal degradation and exocytosis; loss of C9orf72 or SMCR8 impairs autolysosome acidification, leading to aberrant increase of mTOR protein and MTORC1 overactivation. MTORC1 inhibition partially rescues macrophage dysfunction and in vivo immune phenotypes. C9orf72 and Smcr8 KO mice (double KO), lysosomal acidification assay, MTOR/mTORC1 signaling assays, rapamycin treatment, pharmacological lysosomal inhibition Autophagy High 31847700
2021 C9orf72 is a mitochondrial inner-membrane-associated protein; translocation from cytosol to intermembrane space is mediated by the redox-sensitive AIFM1/CHCHD4 pathway. In mitochondria, C9orf72 specifically stabilizes TIMMDC1 (a complex I assembly factor) by recruiting the prohibitin complex to inhibit m-AAA protease-dependent TIMMDC1 degradation. C9orf72 loss impairs mitochondrial complex I function in patient-derived neurons. Mitochondrial fractionation, import assay, Co-IP of C9orf72 with TIMMDC1 and prohibitin complex, m-AAA protease degradation assay, complex I activity measurement in patient neurons Cell Metabolism High 33545050
2021 Poly(PR) expression in neurons activates a p53-driven transcriptional program; p53 ablation completely rescues neurons from poly(PR)-induced degeneration and markedly increases survival in C9orf72 mouse models. p53 activates downstream target Puma to drive neurodegeneration. p53 reduction also rescued axonal degeneration from poly(GR) in patient iPSC motor neurons. Chromatin accessibility profiling (ATAC-seq), transcriptional program analysis, p53 conditional KO mice, C9orf72 mouse model survival, patient iPSC-derived motor neuron survival assay, C9orf72 Drosophila model Cell High 33482083
2022 C9orf72 interacts with synapsin family proteins at synapses via the N-terminal longin domain of C9orf72 and the conserved C domain of synapsin. C9orf72 deficiency reduces excitatory synapse number and synapsin levels, depletes synaptic vesicles from excitatory synapses, and impairs excitatory neurotransmission and network function in hippocampal neurons and KO mice. C9ALS/FTD patient hippocampus shows marked synapsin reduction. Co-IP of endogenous proteins, domain mapping, C9orf72 KO mice, hippocampal neuron cultures, electrophysiology, electron microscopy of synaptic vesicles, neuropathology of patient tissue Acta Neuropathologica High 35876881
2022 C9orf72 localizes to the nucleus and is rapidly recruited to DNA damage sites; C9orf72 deficiency impairs non-homologous end joining (NHEJ) repair through attenuated DNA-PK complex assembly and DDR signaling. In C9orf72-deficient neurons expressing poly-GR, DNA damage accumulates and PARP-1 is excessively activated; PARP-1 inhibition rescues neuronal death. Live imaging of GFP-C9orf72 at DNA damage sites, NHEJ repair assay, DNA-PK complex Co-IP, C9orf72 KO mouse models, PARP-1 inhibitor treatment in cultured neurons Cell Death and Differentiation Medium 36220889
2021 Spliced circular intron RNA (not pre-mRNA) containing expanded G4C2 repeats is stabilized due to defective lariat debranching and serves as the cytoplasmic translation template for DPR proteins; the NXF1-NXT1 pathway mediates nuclear export of this circular intron and modulates toxic DPR production. Single-molecule imaging, circular RNA characterization, lariat debranching assays, NXF1-NXT1 knockdown, DPR production assays in cells Nature Communications High 34389711
2020 RAN translation from C9orf72 G4C2 repeats is regulated by double-stranded RNA-dependent protein kinase (PKR); PKR is activated by structured repeat RNAs and increases RAN protein levels. p-PKR is elevated in C9orf72 ALS/FTD brain; inhibiting PKR with AAV-PKR-K296R or metformin decreases RAN proteins and improves behavior and pathology in C9orf72 BAC mice. Cell-based RAN translation assays, PKR-KO cells, dominant-negative PKR construct, C9orf72 BAC mouse model, AAV delivery, metformin treatment, behavioral phenotyping PNAS High 32690681
2021 DHX36 RNA helicase modulates G4C2 repeat RAN translation; DHX36 depletion suppresses RAN translation in a repeat length-dependent manner, while DHX36 overexpression enhances it. Upregulation of RAN translation via integrated stress response is prevented by DHX36 loss, linking G-quadruplex resolution to DPR production. Luciferase reporter assays in cells and in vitro, DHX36 knockdown/overexpression, integrated stress response activation experiments Journal of Biological Chemistry Medium 34174288
2022 PolyGA DPR proteins sequester VCP (valosin-containing protein), reducing soluble VCP levels and impairing autophagy; polyGA-VCP co-aggregation alters p62 co-localization with polyGA in VCP-depleted cells. VCP sequestration is confirmed in C9orf72 patient autopsy brain tissue. BioID2 proximity labeling interactome, Co-IP, patient brain tissue immunostaining, VCP depletion with polyGA expression, autophagy assays Brain Medium 34534264
2024 G4C2 repeat RNA co-localizes with nuclear speckles and alters their phase separation properties and granule dynamics; the nuclear speckle scaffold protein SRRM2 is sequestered into poly-GR cytoplasmic inclusions in C9-FTD/ALS mouse models and patient tissue, impairing nuclear speckle integrity and inducing global exon skipping and intron retention in iPSC-derived neurons. RNA FISH combined with nuclear speckle immunostaining, mouse model and patient postmortem tissue analysis, SRRM2 Co-IP with poly-GR, iPSC neuron RNA-seq splicing analysis Neuron High 39181135

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 3951 21944778
2011 A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 3521 21944779
2015 The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature 803 26308891
2018 C9orf72-mediated ALS and FTD: multiple pathways to disease. Nature reviews. Neurology 529 30120348
2018 Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons. Nature medicine 460 29400714
2016 The C9orf72 protein interacts with Rab1a and the ULK1 complex to regulate initiation of autophagy. The EMBO journal 322 27334615
2016 C9orf72 BAC Mouse Model with Motor Deficits and Neurodegenerative Features of ALS/FTD. Neuron 304 27112499
2013 Dipeptide repeat protein pathology in C9ORF72 mutation cases: clinico-pathological correlations. Acta neuropathologica 285 24096617
2013 The product of C9orf72, a gene strongly implicated in neurodegeneration, is structurally related to DENN Rab-GEFs. Bioinformatics (Oxford, England) 269 23329412
2020 C9orf72 in myeloid cells suppresses STING-induced inflammation. Nature 237 32814898
2017 The Role of Dipeptide Repeats in C9ORF72-Related ALS-FTD. Frontiers in molecular neuroscience 218 28243191
2020 C9orf72 suppresses systemic and neural inflammation induced by gut bacteria. Nature 207 32483373
2016 A C9ORF72/SMCR8-containing complex regulates ULK1 and plays a dual role in autophagy. Science advances 188 27617292
2015 C9orf72 expansions in frontotemporal dementia and amyotrophic lateral sclerosis. The Lancet. Neurology 188 25638642
2019 Heterochromatin anomalies and double-stranded RNA accumulation underlie C9orf72 poly(PR) toxicity. Science (New York, N.Y.) 172 30765536
2016 The expanding biology of the C9orf72 nucleotide repeat expansion in neurodegenerative disease. Nature reviews. Neuroscience 165 27150398
2020 C9orf72 poly(GR) aggregation induces TDP-43 proteinopathy. Science translational medicine 156 32878979
2021 Suppression of mutant C9orf72 expression by a potent mixed backbone antisense oligonucleotide. Nature medicine 147 34949835
2013 The neuropathology associated with repeat expansions in the C9ORF72 gene. Acta neuropathologica 147 24356984
2016 Gene-specific mitochondria dysfunctions in human TARDBP and C9ORF72 fibroblasts. Acta neuropathologica communications 144 27151080
2021 p53 is a central regulator driving neurodegeneration caused by C9orf72 poly(PR). Cell 137 33482083
2016 There has been an awakening: Emerging mechanisms of C9orf72 mutations in FTD/ALS. Brain research 131 27059391
2017 C9orf72 and RAB7L1 regulate vesicle trafficking in amyotrophic lateral sclerosis and frontotemporal dementia. Brain : a journal of neurology 128 28334866
2017 Age-related penetrance of the C9orf72 repeat expansion. Scientific reports 121 28522837
2021 C9ORF72: What It Is, What It Does, and Why It Matters. Frontiers in cellular neuroscience 118 34025358
2021 Estimated Prevalence and Incidence of Amyotrophic Lateral Sclerosis and SOD1 and C9orf72 Genetic Variants. Neuroepidemiology 118 34247168
2021 C9orf72 regulates energy homeostasis by stabilizing mitochondrial complex I assembly. Cell metabolism 117 33545050
2021 C9orf72 deficiency promotes microglial-mediated synaptic loss in aging and amyloid accumulation. Neuron 113 34133945
2020 Metformin inhibits RAN translation through PKR pathway and mitigates disease in C9orf72 ALS/FTD mice. Proceedings of the National Academy of Sciences of the United States of America 113 32690681
2021 C9orf72 ALS-FTD: recent evidence for dysregulation of the autophagy-lysosome pathway at multiple levels. Autophagy 98 33632058
2018 Disease Mechanisms of C9ORF72 Repeat Expansions. Cold Spring Harbor perspectives in medicine 89 28130314
2017 Autophagy and Its Impact on Neurodegenerative Diseases: New Roles for TDP-43 and C9orf72. Frontiers in molecular neuroscience 78 28611593
2017 Psychiatric Presentations of C9orf72 Mutation: What Are the Diagnostic Implications for Clinicians? The Journal of neuropsychiatry and clinical neurosciences 72 28238272
2017 Antibodies inhibit transmission and aggregation of C9orf72 poly-GA dipeptide repeat proteins. EMBO molecular medicine 69 28351931
2015 Anti-sense DNA d(GGCCCC)n expansions in C9ORF72 form i-motifs and protonated hairpins. Scientific reports 66 26632347
2020 Deficits in verbal fluency in presymptomatic C9orf72 mutation gene carriers-a developmental disorder. Journal of neurology, neurosurgery, and psychiatry 64 32855285
2021 Nuclear export and translation of circular repeat-containing intronic RNA in C9ORF72-ALS/FTD. Nature communications 63 34389711
2018 Synaptic dysfunction and altered excitability in C9ORF72 ALS/FTD. Brain research 62 29453960
2015 An amyloid-like cascade hypothesis for C9orf72 ALS/FTD. Current opinion in neurobiology 62 26555807
2020 Cellular and physiological functions of C9ORF72 and implications for ALS/FTD. Journal of neurochemistry 61 33259633
2023 Divergent single cell transcriptome and epigenome alterations in ALS and FTD patients with C9orf72 mutation. Nature communications 58 37714849
2019 ADAR2 mislocalization and widespread RNA editing aberrations in C9orf72-mediated ALS/FTD. Acta neuropathologica 55 30945056
2018 The C9orf72-interacting protein Smcr8 is a negative regulator of autoimmunity and lysosomal exocytosis. Genes & development 55 29950492
2019 The ALS-FTD-linked gene product, C9orf72, regulates neuronal morphogenesis via autophagy. Autophagy 54 30669939
2016 C9ORF72 is a GDP/GTP exchange factor for Rab8 and Rab39 and regulates autophagy. Small GTPases 54 27494456
2021 Emerging Perspectives on Dipeptide Repeat Proteins in C9ORF72 ALS/FTD. Frontiers in cellular neuroscience 53 33679328
2017 Unraveling the Role of RNA Mediated Toxicity of C9orf72 Repeats in C9-FTD/ALS. Frontiers in neuroscience 51 29326544
2019 Molecular Mechanisms of Neurodegeneration Related to C9orf72 Hexanucleotide Repeat Expansion. Behavioural neurology 49 30774737
2017 C9orf72: At the intersection of lysosome cell biology and neurodegenerative disease. Traffic (Copenhagen, Denmark) 48 28266105
2017 Bidirectional nucleolar dysfunction in C9orf72 frontotemporal lobar degeneration. Acta neuropathologica communications 48 28420437
2019 Synaptic localization of C9orf72 regulates post-synaptic glutamate receptor 1 levels. Acta neuropathologica communications 44 31651360
2019 C9orf72 and smcr8 mutant mice reveal MTORC1 activation due to impaired lysosomal degradation and exocytosis. Autophagy 44 31847700
2017 Genetic models of C9orf72: what is toxic? Current opinion in genetics & development 44 28364657
2017 The Enigmatic Role of C9ORF72 in Autophagy. Frontiers in neuroscience 44 28824365
2017 Longitudinal diffusion imaging across the C9orf72 clinical spectrum. Journal of neurology, neurosurgery, and psychiatry 44 29054917
2019 Nuclear RNA foci from C9ORF72 expansion mutation form paraspeckle-like bodies. Journal of cell science 43 30745340
2019 C9orf72-generated poly-GR and poly-PR do not directly interfere with nucleocytoplasmic transport. Scientific reports 43 31673013
2018 Insights into C9ORF72-Related ALS/FTD from Drosophila and iPSC Models. Trends in neurosciences 43 29729808
2018 Characterization of membrane penetration and cytotoxicity of C9orf72-encoding arginine-rich dipeptides. Scientific reports 43 30143685
2014 Antisense oligonucleotide therapy for the treatment of C9ORF72 ALS/FTD diseases. Molecular neurobiology 43 24809691
2023 Disrupted myelin lipid metabolism differentiates frontotemporal dementia caused by GRN and C9orf72 gene mutations. Acta neuropathologica communications 41 36967384
2020 Widespread intron retention impairs protein homeostasis in C9orf72 ALS brains. Genome research 41 33055097
2016 C9orf72 isoforms in Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration. Brain research 41 27134035
2015 The Spectrum of C9orf72-mediated Neurodegeneration and Amyotrophic Lateral Sclerosis. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 41 25731823
2014 Unconventional features of C9ORF72 expanded repeat in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Neurobiology of aging 40 24836899
2020 C9orf72 associates with inactive Rag GTPases and regulates mTORC1-mediated autophagosomal and lysosomal biogenesis. Aging cell 39 32100453
2018 C9orf72 is essential for neurodevelopment and motility mediated by Cyclin G1. Experimental neurology 38 29522758
2018 C9orf72 Dipeptide Repeats Cause Selective Neurodegeneration and Cell-Autonomous Excitotoxicity in Drosophila Glutamatergic Neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 38 30037833
2021 The RNA helicase DHX36-G4R1 modulates C9orf72 GGGGCC hexanucleotide repeat-associated translation. The Journal of biological chemistry 37 34174288
2018 The Genetics of C9orf72 Expansions. Cold Spring Harbor perspectives in medicine 36 28130313
2020 RNA-mediated toxicity in C9orf72 ALS and FTD. Neurobiology of disease 35 32829028
2013 Modelling C9ORF72 hexanucleotide repeat expansion in amyotrophic lateral sclerosis and frontotemporal dementia. Acta neuropathologica 34 24366528
2022 Expanding Clinical Spectrum of C9ORF72-Related Disorders and Promising Therapeutic Strategies: A Review. Neurology. Genetics 33 35620137
2024 Neuromuscular organoids model spinal neuromuscular pathologies in C9orf72 amyotrophic lateral sclerosis. Cell reports 32 38431841
2018 Gray matter changes in asymptomatic C9orf72 and GRN mutation carriers. NeuroImage. Clinical 32 29845007
2015 DNA Replication Dynamics of the GGGGCC Repeat of the C9orf72 Gene. The Journal of biological chemistry 32 26463209
2016 Development of Therapeutics for C9ORF72 ALS/FTD-Related Disorders. Molecular neurobiology 31 27349438
2022 C9orf72 functions in the nucleus to regulate DNA damage repair. Cell death and differentiation 30 36220889
2017 Disease progression in C9orf72 mutation carriers. Neurology 30 28615433
2017 RNA Misprocessing in C9orf72-Linked Neurodegeneration. Frontiers in cellular neuroscience 30 28744202
2022 An interaction between synapsin and C9orf72 regulates excitatory synapses and is impaired in ALS/FTD. Acta neuropathologica 29 35876881
2015 Bromodomain inhibitors regulate the C9ORF72 locus in ALS. Experimental neurology 27 26099177
2021 FDG-PET in presymptomatic C9orf72 mutation carriers. NeuroImage. Clinical 26 34049163
2016 Recognition of c9orf72 Mutant RNA by Single-Stranded Silencing RNAs. Nucleic acid therapeutics 26 28005462
2015 Emerging role of RNA•DNA hybrids in C9orf72-linked neurodegeneration. Cell cycle (Georgetown, Tex.) 26 25590632
2022 Longitudinal Effects of Asymptomatic C9orf72 Carriership on Brain Morphology. Annals of neurology 25 36511398
2016 C9orf72's Interaction with Rab GTPases-Modulation of Membrane Traffic and Autophagy. Frontiers in cellular neuroscience 25 27774051
2012 Neuroimaging features of C9ORF72 expansion. Alzheimer's research & therapy 25 23153366
2023 Negative regulation of TREM2-mediated C9orf72 poly-GA clearance by the NLRP3 inflammasome. Cell reports 24 36800288
2021 Enhanced insulin signalling ameliorates C9orf72 hexanucleotide repeat expansion toxicity in Drosophila. eLife 24 33739284
2020 Differential Neuropsychological Profile of Patients With Amyotrophic Lateral Sclerosis With and Without C9orf72 Mutation. Neurology 24 33106391
2019 Links Between the C9orf72 Repeat Expansion and Psychiatric Symptoms. Current neurology and neuroscience reports 24 31773397
2025 Amyotrophic lateral sclerosis caused by hexanucleotide repeat expansions in C9orf72: from genetics to therapeutics. The Lancet. Neurology 23 39986312
2023 Roadmap for C9ORF72 in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis: Report on the C9ORF72 FTD/ALS Summit. Neurology and therapy 23 37847372
2022 Interactome screening of C9orf72 dipeptide repeats reveals VCP sequestration and functional impairment by polyGA. Brain : a journal of neurology 23 34534264
2020 RNA dependent suppression of C9orf72 ALS/FTD associated neurodegeneration by Matrin-3. Acta neuropathologica communications 23 33129345
2021 Altered Phase Separation and Cellular Impact in C9orf72-Linked ALS/FTD. Frontiers in cellular neuroscience 22 33967699
2014 Biomarker development for C9orf72 repeat expansion in ALS. Brain research 22 25261695
2024 Disruption of nuclear speckle integrity dysregulates RNA splicing in C9ORF72-FTD/ALS. Neuron 21 39181135
2021 Ribosome profiling reveals novel regulation of C9ORF72 GGGGCC repeat-containing RNA translation. RNA (New York, N.Y.) 21 34848561