Affinage

C9ORF72

Guanine nucleotide exchange factor C9orf72 · UniProt Q96LT7

Length
481 aa
Mass
54.3 kDa
Annotated
2026-06-09
100 papers in source corpus 29 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

C9ORF72 is a DENN-domain protein that organizes membrane trafficking, lysosomal homeostasis, and autophagy, and its disruption by a noncoding GGGGCC hexanucleotide repeat expansion causes ALS/FTD through combined loss-of-function and RNA/protein gain-of-function mechanisms (PMID:21944778, PMID:21944779, PMID:23329412). The long C9ORF72 isoform forms a stable tripartite complex with SMCR8 and WDR41 that acts as a guanine-nucleotide exchange factor for Rab GTPases including Rab8a and Rab39b, and engages Rab1a and the ULK1–RB1CC1–ATG13–ATG101 initiation complex—binding ATG13 directly through its isoform-specific C-terminal DENN/dDENN domain—to drive autophagy and lysosomal biogenesis (PMID:27334615, PMID:27494456, PMID:30669939). Through its DENN domain it also binds inactive Rag GTPases to tune mTORC1 signaling and MiT/TFE-dependent lysosomal gene programs, and loss of C9ORF72/SMCR8 impairs autolysosome acidification and degradation while enhancing lysosomal exocytosis (PMID:32100453, PMID:31847700, PMID:29950492). Beyond the lysosome, C9ORF72 localizes to the mitochondrial inner membrane where it recruits the prohibitin complex to protect TIMMDC1 from m-AAA protease degradation and sustain complex I assembly (PMID:33545050), to the nucleus where it is recruited to DNA damage sites to promote DNA-PK assembly and NHEJ repair (PMID:36220889), and to synapses where its N-terminal longin domain binds synapsin to support excitatory neurotransmission and synaptic vesicle pools (PMID:35876881). In myeloid cells C9ORF72 loss impairs autolysosomal degradation of STING, driving type I interferon and JAK-STAT hyperactivation and autoinflammation (PMID:32814898, PMID:37250330), and alters microglial homeostasis and synaptic pruning (PMID:34133945). The repeat expansion reduces C9ORF72 levels (haploinsufficiency) and generates toxic RNA foci that mislocalize RanGAP1 and disrupt nucleocytoplasmic transport (PMID:26308891), while repeat-associated non-AUG translation—templated by a spliced circular intron and regulated by PKR and DHX36—produces dipeptide repeat proteins; arginine-rich PR/GR species bind karyopherin-β2, disrupt HP1α-dependent heterochromatin, sequester the nuclear speckle scaffold SRRM2, and promote TDP-43 aggregation (PMID:34489423, PMID:30765536, PMID:32878979, PMID:39181135, PMID:32690681, PMID:34174288, PMID:34389711).

Mechanistic history

Synthesis pass · year-by-year structured walk · 26 steps
  1. 2011 High

    Established the genetic cause of C9-ALS/FTD and framed the dual disease logic, showing the GGGGCC expansion both lowers a C9ORF72 transcript (loss-of-function) and forms nuclear RNA foci (RNA gain-of-function).

    Evidence Genetic linkage, repeat expansion identification, transcript analysis, and RNA foci detection in patient tissue

    PMID:21944778 PMID:21944779

    Open questions at the time
    • Did not define the normal protein function lost
    • Did not establish which mechanism dominates pathogenesis
  2. 2013 Low

    Provided the first hypothesis for C9ORF72 molecular function by recognizing it as a DENN-domain Rab-GEF-like protein, predicting a role in membrane trafficking.

    Evidence Sensitive computational homology searches

    PMID:23329412

    Open questions at the time
    • Computational prediction only with no functional validation in this study
    • No Rab substrate identified
    • No subcellular localization tested
  3. 2015 High

    Demonstrated an RNA gain-of-function pathway, showing repeat RNA binds and mislocalizes RanGAP1 to impair nucleocytoplasmic transport, and that this is pharmacologically reversible.

    Evidence Drosophila genetic screen, RanGAP–HRE RNA binding, patient iPSC neuron and brain immunofluorescence, nuclear import assays, small molecule/ASO rescue

    PMID:26308891

    Open questions at the time
    • Relative contribution of foci vs DPRs to transport defect not resolved
    • Does not address protein loss-of-function arm
  4. 2015 Medium

    Localized endogenous C9ORF72 to neuronal puncta, actin-rich growth structures, and synaptosomes, providing early evidence for a synaptic and developmentally regulated role.

    Evidence Cellular fractionation, immunofluorescence time-course, and synaptosome preparation from mouse brain

    PMID:26408000

    Open questions at the time
    • No molecular partner at synapses identified here
    • Isoform-specific localization not mechanistically explained
  5. 2016 High

    Converted the GEF prediction into function, defining the C9ORF72–SMCR8–WDR41 complex as a Rab8a/Rab39b GEF and as a Rab1a effector controlling ULK1-complex trafficking and autophagy initiation.

    Evidence Co-IP, pulldowns, in vitro GEF assays, and autophagy flux/p62 assays in cell lines, primary neurons, and patient iNeurons

    PMID:27334615 PMID:27494456

    Open questions at the time
    • GEF activity characterized in single labs
    • Quantitative kinetics of nucleotide exchange not established
  6. 2018 High

    Placed C9ORF72 in vesicle trafficking and lysosomal biogenesis in motor neurons and linked its reduction to glutamate receptor accumulation and excitotoxic neurodegeneration rescuable by active RAB5.

    Evidence Patient iPSC-derived iMNs with endosome, trafficking, and lysosomal assays plus constitutively active RAB5 rescue and mouse validation

    PMID:29400714

    Open questions at the time
    • Direct Rab5 GEF relationship not biochemically defined here
    • Link between trafficking defect and receptor accumulation correlative
  7. 2018 High

    Defined complex architecture and an immune-suppressive role, showing C9ORF72 stabilizes SMCR8 to assemble the tripartite complex and that the complex restrains lysosomal exocytosis and autoimmunity.

    Evidence Quantitative MS interactomics, Smcr8 mutant mice, and LAMP1 surface/secretion assays in macrophages

    PMID:29950492

    Open questions at the time
    • Molecular control of exocytosis not fully defined
    • Connection to specific Rab effectors of exocytosis unresolved
  8. 2019 High

    Mapped a direct, isoform-specific autophagy mechanism, placing C9ORF72 as an ATG13-binding component of the ULK1 initiation complex via its C-terminal DENN/dDENN domain.

    Evidence Quantitative proteomics, Co-IP with domain mapping, c9orf72 KO mouse neurons, LC3-II flux, and isoform-specific rescue of autophagy and dendritic phenotypes

    PMID:30669939

    Open questions at the time
    • Short isoform function remains undefined
    • How ATG13 binding integrates with Rab-GEF activity unclear
  9. 2019 Medium

    Connected C9ORF72 to nutrient signaling by showing its DENN domain selectively binds inactive Rag GTPases to modulate mTORC1 and MiT/TFE lysosomal transcription.

    Evidence Co-IP with active/inactive Rag specificity, mTORC1 and MiT/TFE nuclear translocation assays, and active-Rag rescue

    PMID:32100453

    Open questions at the time
    • Single-lab Co-IP without structural validation
    • Whether C9ORF72 acts as a GEF/GDF for Rags not established
  10. 2017 Medium

    Linked the expansion to genome instability, showing R-loop and double-strand break accumulation downstream of p62-mediated impairment of H2A ubiquitylation and ATM signaling.

    Evidence R-loop (S9.6) and γH2AX detection across rat neurons, human cells, and patient spinal cord, ATM and H2A ubiquitylation assays, and viral CNS expression model

    PMID:28714954

    Open questions at the time
    • Single-lab mechanism
    • Separation of RNA vs DPR contribution to DSBs incomplete
  11. 2019 High

    Defined a chromatin gain-of-function for arginine-rich DPRs, showing poly(PR) binds heterochromatin and disrupts HP1α phase behavior, histone methylation, and nuclear lamina, derepressing repetitive elements.

    Evidence (PR)50-GFP mouse model with chromatin binding, phase separation, epigenetic, and dsRNA readouts

    PMID:30765536

    Open questions at the time
    • Disease relevance of supraphysiologic PR expression
    • Link to downstream neuronal death not fully traced
  12. 2019 High

    Established a causal lysosome-to-mTORC1 axis in immune cells, showing C9orf72/Smcr8 loss disrupts autolysosome acidification and overactivates MTORC1, rescuable by mTORC1 inhibition.

    Evidence c9orf72/smcr8 double-KO mice with lysosomal pH, MTORC1 signaling assays, and rapamycin rescue

    PMID:31847700

    Open questions at the time
    • Apparent opposing mTORC1 effects across studies not reconciled
    • Cell-type specificity of mTORC1 regulation unresolved
  13. 2020 High

    Identified a myeloid autoinflammation mechanism, showing C9ORF72 loss impairs autolysosomal STING degradation to drive type I interferon hyperactivation and inflammation reversible by STING blockade.

    Evidence Myeloid-specific C9orf72 KO mice, IFN profiling, STING activation and autolysosomal degradation assays, and STING-inhibitor rescue in mice and patient macrophages

    PMID:32814898

    Open questions at the time
    • Mechanism of STING delivery to autolysosomes not detailed
    • Relevance to neuronal pathology indirect
  14. 2020 High

    Extended the immune phenotype to brain, showing C9orf72-deficient microglia shift to an inflammatory state with enhanced synaptic pruning that impairs cognition while paradoxically clearing amyloid.

    Evidence Microglia-specific KO with transcriptomics, synaptic pruning quantification, behavior, and amyloid model crossing

    PMID:34133945

    Open questions at the time
    • Molecular driver of enhanced pruning not pinpointed
    • Link to type I IFN signature causal chain incomplete
  15. 2020 Medium

    Showed C9ORF72 loss-of-function is insufficient alone for ALS phenotypes in rat but synergizes with excitotoxicity, supporting a multi-hit pathogenic model.

    Evidence C9orf72 KO rat combined with kainic acid excitotoxicity, motor and histological assays, and RNA-seq

    PMID:32745320

    Open questions at the time
    • Species/strain dependence of phenotype
    • Molecular basis of excitotoxic synergy undefined
  16. 2020 High

    Defined an RNA-independent DPR toxicity route, showing poly(GR) directly drives TDP-43 aggregation and nuclear transport disruption, with ASO rescue tying it back to the repeat.

    Evidence poly(GR)-TDP-43 Co-IP, RNA-independent sequestration assays, GR mouse model, and ASO treatment

    PMID:32878979

    Open questions at the time
    • Whether GR initiates or amplifies TDP-43 pathology unresolved
    • Quantitative contribution relative to RNA foci unclear
  17. 2021 High

    Revealed a mitochondrial function for C9ORF72, showing inner-membrane localization where it recruits prohibitin to protect TIMMDC1 from m-AAA protease degradation and sustain complex I.

    Evidence Mitochondrial fractionation, Co-IP of C9orf72–TIMMDC1–prohibitin, protease degradation and complex I activity assays, and patient neuron assessment

    PMID:33545050

    Open questions at the time
    • Relationship of mitochondrial pool to the SMCR8/WDR41 complex unknown
    • Trigger for cytosol-to-mitochondria translocation in disease unresolved
  18. 2021 High

    Provided biophysical detail for PR-mediated transport disruption, showing poly(PR) binds karyopherin-β2 at its NLS site 1:1 to impair nuclear import receptor phase-modifier function.

    Evidence ITC, size-exclusion chromatography, and NMR mapping of Kapβ2–PR interaction

    PMID:34489423

    Open questions at the time
    • In vivo consequence of this specific interaction not quantified here
    • Selectivity across import receptors not fully mapped
  19. 2021 High

    Identified the regulatory machinery of RAN translation, showing PKR activation by structured repeat RNA and DHX36 helicase activity control DPR production, with PKR inhibition therapeutic in mice.

    Evidence PKR activation/dominant-negative and KO assays, DHX36 gain/loss reporter assays, and AAV-PKR-K296R/metformin rescue in BAC transgenic mice

    PMID:32690681 PMID:34174288

    Open questions at the time
    • DHX36 findings from single-lab reporter assays
    • Integration of PKR and DHX36 in same pathway not fully tested
  20. 2021 Medium

    Pinpointed the DPR translation template and its export route, showing a spliced circular intron stabilized by defective lariat debranching is exported by NXF1-NXT1 to template DPR synthesis.

    Evidence Single molecule imaging, circular RNA/lariat debranching characterization, and NXF1-NXT1 perturbation with DPR reporters

    PMID:34389711

    Open questions at the time
    • Single-lab characterization
    • Relative DPR contribution from circular intron vs pre-mRNA unquantified
  21. 2021 High

    Identified p53 as a central effector node, showing poly(PR) activates a p53–Puma program whose ablation rescues neurodegeneration across multiple models.

    Evidence ATAC-seq/transcriptomics, p53 KO rescue in C9orf72 mice, axonal degeneration, iPSC motor neuron survival, and fly model

    PMID:33482083

    Open questions at the time
    • Upstream signal linking PR to p53 activation undefined
    • Whether p53 axis operates downstream of loss-of-function unclear
  22. 2021 High

    Established a direct synaptic mechanism, mapping C9ORF72's N-terminal longin domain to synapsin and showing its loss reduces excitatory synapses, neurotransmission, and synaptic vesicle pools.

    Evidence Endogenous Co-IP with domain mapping, KO mouse hippocampal electrophysiology and EM, and patient tissue immunohistochemistry

    PMID:35876881

    Open questions at the time
    • Functional consequence of synapsin binding on vesicle cycling not fully resolved
    • Relation to trafficking/autophagy roles unclear
  23. 2022 Medium

    Defined a nuclear DNA-repair function, showing C9ORF72 is recruited to damage sites and promotes DNA-PK assembly and NHEJ, with its loss exacerbating poly-GR toxicity via PARP-1 overactivation.

    Evidence Live imaging of nuclear recruitment, NHEJ and DNA-PK assembly assays, KO mouse with poly-GR co-expression, and PARP-1 inhibitor rescue

    PMID:36220889

    Open questions at the time
    • Single-lab mechanism
    • How a trafficking protein engages NHEJ machinery structurally undefined
  24. 2023 Medium

    Extended inflammatory signaling, showing C9ORF72 loss elevates STING and hyperactivates JAK-STAT through compromised lysosome integrity, rescuable by JAK inhibition.

    Evidence JAK-STAT and STING assays in KO cells/mice, lysosome integrity assays, and JAK-inhibitor rescue in vitro and in vivo

    PMID:37250330

    Open questions at the time
    • Single-lab study
    • Overlap with prior STING/IFN mechanism not fully integrated
  25. 2023 Medium

    Linked the repeat to its own transcriptional silencing, showing HRE DNA binds DAXX and promotes its phase separation, driving chromatin remodeling that suppresses C9orf72 expression.

    Evidence HRE DNA–DAXX binding, LLPS assays, ChIP/histone modification analysis, and DAXX knockdown rescue in patient motor neurons

    PMID:36822200

    Open questions at the time
    • Single-lab study
    • Contribution of DAXX-driven silencing to overall haploinsufficiency unquantified
  26. 2024 Medium

    Identified nuclear speckle dysfunction as a toxicity mechanism, showing repeat RNA alters speckle phase properties and poly-GR sequesters SRRM2, causing splicing defects and neurotoxicity.

    Evidence Single molecule imaging, phase separation assays, SRRM2 immunohistochemistry in mouse and patient tissue, and iPSC neuron splicing/toxicity analysis

    PMID:39181135

    Open questions at the time
    • Single-lab study
    • Causal ranking among speckle, transport, and TDP-43 mechanisms unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how the distinct subcellular activities of C9ORF72 (lysosomal GEF, mitochondrial complex I support, nuclear NHEJ, synaptic synapsin binding) are coordinated, and how loss-of-function and the multiple gain-of-function arms are quantitatively weighted in driving neurodegeneration.
  • No structure of the C9ORF72-SMCR8-WDR41 complex with Rab substrates reported in the corpus
  • Integration of immune, neuronal, and metabolic phenotypes into one pathogenic sequence lacking
  • Relative therapeutic value of targeting loss vs RNA vs DPR mechanisms unestablished

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005764 lysosome 4 GO:0005634 nucleus 2 GO:0005739 mitochondrion 1 GO:0005768 endosome 1 GO:0005829 cytosol 1
Pathway
R-HSA-9612973 Autophagy 3 R-HSA-162582 Signal Transduction 2 R-HSA-1643685 Disease 2 R-HSA-168256 Immune System 2 R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-73894 DNA Repair 2
Partners
ATG13RAB1ARAB8ARANGAP1SMCR8SYNAPSINTIMMDC1WDR41
Complex memberships
C9ORF72-SMCR8-WDR41 complexULK1-RB1CC1-ATG13-ATG101 autophagy initiation complex

Evidence

Reading pass · 28 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 leads to loss of one alternatively spliced C9ORF72 transcript and to formation of nuclear RNA foci, establishing both loss-of-function and RNA gain-of-function as disease mechanisms. Genetic linkage analysis, repeat expansion identification, transcript analysis, RNA foci detection in patient tissue Neuron High 21944778 21944779
2013 C9ORF72 protein is structurally related to DENN (Differentially Expressed in Normal and Neoplasia) Rab-GEF proteins by sensitive homology searches, suggesting it functions as a GDP/GTP exchange factor for Rab GTPases to regulate membrane trafficking. Computational homology searches (bioinformatics structural prediction) Bioinformatics (Oxford, England) Low 23329412
2015 The C9orf72 repeat expansion disrupts nucleocytoplasmic transport: RanGAP1 physically interacts with HRE RNA and is mislocalized in HRE-expressing flies, C9orf72 ALS patient iPSC-derived neurons, and patient brain tissue. Nuclear import is impaired as a result of HRE expression and is rescued by small molecules and antisense oligonucleotides targeting HRE G-quadruplexes. Candidate-based genetic screen in Drosophila, physical interaction assay (RanGAP-HRE RNA binding), immunofluorescence in patient iPSC neurons and brain tissue, nuclear import assay, small molecule/ASO rescue experiments Nature High 26308891
2016 C9orf72 interacts with Rab1a and the ULK1 autophagy initiation complex, and as a Rab1a effector controls initiation of autophagy by regulating Rab1a-dependent trafficking of the ULK1 complex to the phagophore. Reduction of C9orf72 in cell lines and primary neurons attenuates autophagy and causes accumulation of p62-positive puncta. Co-immunoprecipitation, pulldown assays, autophagy flux assays in cell lines and primary neurons, knockdown experiments, patient-derived iNeurons The EMBO journal High 27334615
2016 C9ORF72, together with SMCR8 and WDR41, forms a stable tripartite complex and acts as a GDP/GTP exchange factor (GEF) for the small RAB GTPases Rab8a and Rab39b, regulating macroautophagy. Decreased C9orf72 expression in neuronal cultures leads to autophagy dysfunction characterized by accumulation of p62/SQSTM1 aggregates. Co-immunoprecipitation identifying C9orf72-SMCR8-WDR41 complex, GEF activity assay for Rab8a and Rab39b, autophagy assays with p62 accumulation in neuronal cultures Small GTPases Medium 27494456
2018 C9orf72's long isoform complexes with and stabilizes SMCR8, which further enables interaction with WDR41, forming a tripartite complex. This complex suppresses autoimmunity and negatively regulates lysosomal exocytosis; loss of C9orf72 results in increased surface LAMP1 expression and enhanced secretion of lysosomal components in macrophages. Quantitative mass spectrometry-based proteomics in motor neurons, Smcr8 loss-of-function mutant mice, LAMP1 surface expression and lysosomal secretion assays in macrophages Genes & development High 29950492
2018 C9ORF72 interacts with endosomes and is required for normal vesicle trafficking and lysosomal biogenesis in motor neurons. Repeat expansion-reduced C9orf72 expression triggers neurodegeneration via accumulation of glutamate receptors (excitotoxicity) and impaired clearance of neurotoxic dipeptide repeat proteins. Restoring C9orf72 levels or augmenting function with constitutively active RAB5 rescued patient neuron survival. Human induced motor neurons (iMNs) from patient iPSCs, endosome interaction assays, vesicle trafficking assays, lysosomal biogenesis assays, RAB5 rescue experiments Nature medicine High 29400714
2019 C9orf72 is a component of the ULK1-RB1CC1-ATG13-ATG101 autophagy initiation complex, interacting directly with ATG13 via the isoform-specific carboxyl-terminal DENN and dDENN domain. C9orf72 knockout neurons show reduced LC3-II puncta and reduced ULK1 levels, indicating loss of C9orf72 impairs basal autophagy. Expression of the long C9orf72 isoform (but not the short isoform) rescues autophagy and dendritic arborization phenotypes. Quantitative proteomic analysis, Co-IP (C9orf72-ATG13 interaction), c9orf72 knockout mouse neurons, LC3-II autophagy flux assay, dendritic morphology quantification, isoform rescue experiments Autophagy High 30669939
2019 C9orf72 DENN domain specifically binds to inactive Rag GTPases (but not active Rag GTPases), thereby affecting Rag/raptor/mTOR complex function and mTORC1 activity. Loss of C9orf72 leads to accumulation of lysosomes, autophagosomes, and autolysosomes, associated with suppressed mTORC1 activity and enhanced nuclear translocation of MITF, TFE3, and TFEB. Co-immunoprecipitation (C9orf72-Rag GTPase interaction), lysosomal biogenesis assays, mTORC1 activity assays, nuclear translocation assays for MiT/TFE members, rescue with active Rag GTPases Aging cell Medium 32100453
2019 C9orf72 and Smcr8 double-knockout mice show impaired lysosomal degradation and exocytosis due to disrupted autolysosome acidification, leading to aberrant MTOR protein accumulation and MTORC1 signaling overactivation. Inhibition of hyperactive MTORC1 partially rescued macrophage dysfunction. c9orf72 and smcr8 double-knockout (dKO) mice, lysosomal pH/acidification assays, MTORC1 signaling assays, rapamycin/pharmacological MTORC1 inhibition rescue Autophagy High 31847700
2020 Loss of C9orf72 from myeloid cells alone is sufficient to cause age-dependent lymphoid hypertrophy and autoinflammation. C9orf72-deficient dendritic cells show early type I interferon response hyperactivation, and C9orf72-deficient myeloid cells are selectively hyperresponsive to STING activators. Degradation of STING through the autolysosomal pathway is diminished in C9orf72-deficient myeloid cells; blocking STING suppresses the hyperactive interferon responses and inflammation. Myeloid cell-specific C9orf72 knockout mice, dendritic cell isolation with IFN response profiling, STING pathway activation assays, autolysosomal degradation assays, STING inhibitor rescue in mice and patient macrophages Nature High 32814898
2020 C9orf72 deficiency in mice leads to a change in microglial homeostatic signature and transition to an inflammatory state with enhanced type I IFN response. C9orf72-depleted microglia trigger age-dependent enhanced cortical synaptic pruning, leading to altered learning and memory, and paradoxically improve amyloid plaque clearance while worsening synapse loss. C9orf72 conditional knockout in microglia, microglial transcriptomic profiling, synaptic pruning quantification, behavioral testing, amyloid mouse model crossing Neuron High 34133945
2021 C9orf72 is a mitochondrial inner-membrane-associated protein that regulates energy homeostasis via oxidative phosphorylation. C9orf72 translocation from the cytosol to the inter-membrane space is mediated by the redox-sensitive AIFM1/CHCHD4 pathway. In mitochondria, C9orf72 specifically stabilizes TIMMDC1 (a crucial factor for OXPHOS complex I assembly) by directly recruiting the prohibitin complex to inhibit m-AAA protease-dependent degradation of TIMMDC1. Mitochondrial complex I function is impaired in C9orf72-linked ALS/FTD patient-derived neurons. Mitochondrial fractionation, Co-IP (C9orf72-TIMMDC1-prohibitin complex), m-AAA protease degradation assay, OXPHOS complex I activity assay, patient iPSC-derived neuron functional assessment Cell metabolism High 33545050
2021 C9orf72 interacts with synapsin family proteins at synapses via its N-terminal longin domain (interacting with the conserved C domain of synapsin). C9orf72 deficiency reduces the number of excitatory synapses, decreases synapsin levels at remaining synapses, impairs excitatory neurotransmission, and depletes synaptic vesicles from excitatory synapses. C9orf72 haploinsufficiency in patient hippocampus shows marked synapsin reduction. Co-IP of endogenous C9orf72-synapsin in synapses, domain mapping by pulldown, C9orf72 knockout mouse hippocampal analysis, electrophysiological recordings, electron microscopy of synaptic vesicles, patient postmortem tissue immunohistochemistry Acta neuropathologica High 35876881
2022 C9orf72 localizes to the nucleus and is rapidly recruited to sites of DNA damage. C9orf72 deficiency results in impaired non-homologous end joining (NHEJ) repair through attenuated DNA-PK complex assembly and DNA damage response signaling. C9orf72 deficiency exacerbates poly-GR-induced neurodegeneration and leads to PARP-1 overactivation; PARP-1 inhibition rescued neuronal death. Immunofluorescence live imaging of nuclear C9orf72 at DNA damage sites, NHEJ repair assay, DNA-PK complex assembly assay, KO mouse model with poly-GR co-expression, PARP-1 inhibitor rescue in cultured neurons Cell death and differentiation Medium 36220889
2017 C9orf72 repeat expansion causes elevated levels of DNA-RNA hybrids (R-loops) and double-strand breaks. Defective ATM-mediated DNA repair is a consequence of P62 accumulation, which impairs H2A ubiquitylation and perturbs ATM signaling. Expression of C9orf72-related RNA and dipeptide repeats in mouse CNS increases double-strand breaks and ATM defects, triggering neurodegeneration. R-loop detection (S9.6 antibody), DSB quantification (γH2AX) in rat neurons/human cells/patient spinal cord, ATM signaling assays, P62 accumulation analysis, H2A ubiquitylation assay, viral vector mouse CNS expression model Nature neuroscience Medium 28714954
2015 C9ORF72 protein is localized as puncta throughout neurons including actin-rich structures such as filopodia and growth cones, and is present in synaptosome preparations from adult mouse brain, indicating a role at synapses. Different C9orf72 isoforms show differential nuclear vs. cytoplasmic expression over development. Cellular fractionation, immunofluorescence in cultured cortical neurons and brain tissue (developmental time-course), synaptosome preparation from adult mouse brain Acta neuropathologica communications Medium 26408000
2023 Loss of C9ORF72 leads to hyperactivation of the JAK-STAT pathway and increased STING protein levels. Compromised lysosome integrity in C9ORF72-deficient cells contributes to JAK/STAT-dependent inflammatory responses. JAK inhibitor treatment rescues enhanced inflammatory phenotypes in C9ORF72-deficient cells and mice. JAK-STAT pathway activation assays in C9orf72 KO cells/mice, STING protein level measurement, lysosome integrity assays, JAK inhibitor rescue experiments in vitro and in vivo iScience Medium 37250330
2021 Arginine-rich poly-dipeptides (PR) from C9orf72 tightly bind karyopherin-β2 (Kapβ2) at a 1:1 ratio, targeting the NLS binding site of Kapβ2. This impedes NIR (nuclear import receptor) function as a phase modifier of RNA-binding proteins, disabling phase transitions of RBPs. Isothermal titration calorimetry (ITC), size-exclusion chromatography, nuclear magnetic resonance (NMR) of Kapβ2 perturbed by PR poly-dipeptides, comparison with designed NLS peptide Nature communications High 34489423
2019 Poly(PR) dipeptide repeat protein from C9orf72 binds DNA, localizes to heterochromatin, and causes HP1α liquid-phase disruptions, decreases in HP1α expression, abnormal histone methylation, and nuclear lamina invaginations. These lead to repetitive element expression and double-stranded RNA accumulation. (PR)50-GFP mouse model (brain-wide expression), chromatin binding assays, HP1α phase separation assays, histone methylation analysis, nuclear lamina imaging, dsRNA detection Science (New York, N.Y.) High 30765536
2020 Poly(GR) from C9orf72 repeat expansion promotes aggregation of endogenous TDP-43 in an RNA-independent manner, causing cytoplasmic TDP-43 inclusion formation. Poly(GR) also causes mislocalization of nucleocytoplasmic transport factors and nuclear pore complex proteins, leading to aberrant TDP-43 cytoplasmic accumulation and co-aggregation with poly(GR). ASO targeting of G4C2 repeats reduced poly(GR) burden and TDP-43 pathology. Co-immunoprecipitation (poly(GR)-TDP-43), RNA-independent sequestration assay, GFP-(GR)200 mouse model with nucleocytoplasmic transport factor localization analysis, ASO treatment with biochemical and pathological readouts Science translational medicine High 32878979
2023 The C9orf72 HRE DNA binds to DAXX protein and promotes its liquid-liquid phase separation, which reorganizes genomic structures. HRE-dependent nuclear accumulation of DAXX drives chromatin remodeling and epigenetic changes (histone hypermethylation and hypoacetylation). DAXX suppresses basal and stress-inducible expression of C9orf72 via chromatin remodeling and epigenetic modifications of the C9orf72 major transcript promoter. DNA-protein binding assay (HRE DNA-DAXX), LLPS assay, chromatin immunoprecipitation, histone modification analysis, DAXX knockdown rescue in patient-derived motor neurons Neuron Medium 36822200
2024 (GGGGCC)n 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 model and patient postmortem tissues. Impaired nuclear speckle integrity induces global exon skipping and intron retention in human iPSC-derived neurons, causing neuronal toxicity. Single molecule imaging, co-localization assays (repeat RNA-nuclear speckles), phase separation assays, SRRM2 immunohistochemistry in mouse model and patient tissue, iPSC-derived neuron RNA splicing analysis, neuronal toxicity assay Neuron Medium 39181135
2021 RAN translation of C9orf72 G4C2 repeats is regulated by double-stranded RNA-dependent protein kinase (PKR): G4C2 expansion RNAs activate PKR, leading to increased levels of multiple RAN proteins. Blocking PKR reduces RAN protein levels. p-PKR is elevated in C9orf72 ALS/FTD human and mouse brains, and inhibiting PKR (via AAV-PKR-K296R or metformin) decreases RAN proteins and improves behavior and pathology in C9orf72 BAC transgenic mice. PKR activation assays with structured repeat RNAs, PKR-K296R dominant-negative blockade, PKR-KO cells, RAN protein level quantification, C9orf72 BAC transgenic mouse AAV injection and metformin treatment with behavioral/pathological endpoints Proceedings of the National Academy of Sciences of the United States of America High 32690681
2021 The RNA helicase DHX36 (G4R1) modulates C9orf72 G4C2 repeat-associated non-AUG (RAN) translation: DHX36 depletion suppresses RAN translation in a repeat length-dependent manner, while DHX36 overexpression enhances RAN translation from G4C2 reporter RNAs. DHX36 is required for integrated stress response-triggered upregulation of RAN translation. Luciferase reporter assays in cells and in vitro, DHX36 depletion and overexpression experiments, integrated stress response activation assays The Journal of biological chemistry Medium 34174288
2021 Neurons expressing poly(PR) from the C9orf72 repeat expansion activate a highly specific p53-dependent transcriptional program. Ablating p53 in mice completely rescues neurons from poly(PR)-induced degeneration and markedly increases survival in a C9orf72 mouse model. p53 activates downstream Puma to drive neurodegeneration. Chromatin accessibility profiling (ATAC-seq) and transcriptomics in degenerating neurons, p53 knockout in C9orf72 mouse model, axonal degeneration assay, patient iPSC motor neuron survival assay, C9orf72 fly model Cell High 33482083
2021 Spliced circular intron (not pre-mRNA) containing G4C2 repeats serves as the translation template for dipeptide repeat proteins in C9ORF72 ALS/FTD. The spliced intron is stabilized in circular form due to defective lariat debranching. The NXF1-NXT1 pathway plays an important role in nuclear export of this circular intron and modulates toxic DPR production. Single molecule imaging of repeat RNA species, circular RNA characterization (lariat debranching assay), NXF1-NXT1 pathway perturbation, DPR production assays with reporter system Nature communications Medium 34389711
2020 C9orf72 deficiency in macrophages results in impaired lysosomal degradation and exocytosis. C9orf72 loss of function alone (in rat) does not cause ALS phenotypes, but C9orf72 ablation combined with kainic acid-induced excitotoxicity produces motor deficits, motor neuron loss, Golgi complex fragmentation, and abnormal vesicle trafficking. C9orf72 gene deletion in rats, kainic acid excitotoxicity model, motor function testing, motor neuron histology, vesicle trafficking assays, RNA sequencing The FEBS journal Medium 32745320

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 3977 21944778
2011 A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 3542 21944779
2015 The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature 812 26308891
2018 C9orf72-mediated ALS and FTD: multiple pathways to disease. Nature reviews. Neurology 536 30120348
2018 Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons. Nature medicine 465 29400714
2016 The C9orf72 protein interacts with Rab1a and the ULK1 complex to regulate initiation of autophagy. The EMBO journal 327 27334615
2016 C9orf72 BAC Mouse Model with Motor Deficits and Neurodegenerative Features of ALS/FTD. Neuron 306 27112499
2013 Dipeptide repeat protein pathology in C9ORF72 mutation cases: clinico-pathological correlations. Acta neuropathologica 287 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 222 28243191
2020 C9orf72 suppresses systemic and neural inflammation induced by gut bacteria. Nature 217 32483373
2015 C9orf72 expansions in frontotemporal dementia and amyotrophic lateral sclerosis. The Lancet. Neurology 191 25638642
2019 Heterochromatin anomalies and double-stranded RNA accumulation underlie C9orf72 poly(PR) toxicity. Science (New York, N.Y.) 173 30765536
2020 C9orf72 poly(GR) aggregation induces TDP-43 proteinopathy. Science translational medicine 162 32878979
2021 Suppression of mutant C9orf72 expression by a potent mixed backbone antisense oligonucleotide. Nature medicine 150 34949835
2017 C9orf72 expansion disrupts ATM-mediated chromosomal break repair. Nature neuroscience 148 28714954
2013 The neuropathology associated with repeat expansions in the C9ORF72 gene. Acta neuropathologica 148 24356984
2016 Gene-specific mitochondria dysfunctions in human TARDBP and C9ORF72 fibroblasts. Acta neuropathologica communications 146 27151080
2021 p53 is a central regulator driving neurodegeneration caused by C9orf72 poly(PR). Cell 139 33482083
2017 Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementia. The Journal of clinical investigation 136 28737506
2016 There has been an awakening: Emerging mechanisms of C9orf72 mutations in FTD/ALS. Brain research 131 27059391
2017 Age-related penetrance of the C9orf72 repeat expansion. Scientific reports 123 28522837
2021 C9ORF72: What It Is, What It Does, and Why It Matters. Frontiers in cellular neuroscience 122 34025358
2021 C9orf72 regulates energy homeostasis by stabilizing mitochondrial complex I assembly. Cell metabolism 121 33545050
2021 Estimated Prevalence and Incidence of Amyotrophic Lateral Sclerosis and SOD1 and C9orf72 Genetic Variants. Neuroepidemiology 121 34247168
2021 C9orf72 deficiency promotes microglial-mediated synaptic loss in aging and amyloid accumulation. Neuron 114 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 101 33632058
2018 Disease Mechanisms of C9ORF72 Repeat Expansions. Cold Spring Harbor perspectives in medicine 90 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 74 28238272
2021 Nuclear export and translation of circular repeat-containing intronic RNA in C9ORF72-ALS/FTD. Nature communications 65 34389711
2020 Deficits in verbal fluency in presymptomatic C9orf72 mutation gene carriers-a developmental disorder. Journal of neurology, neurosurgery, and psychiatry 65 32855285
2020 Cellular and physiological functions of C9ORF72 and implications for ALS/FTD. Journal of neurochemistry 63 33259633
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
2023 Divergent single cell transcriptome and epigenome alterations in ALS and FTD patients with C9orf72 mutation. Nature communications 60 37714849
2018 C9orf72-FTD/ALS pathogenesis: evidence from human neuropathological studies. Acta neuropathologica 59 30368547
2018 The C9orf72-interacting protein Smcr8 is a negative regulator of autoimmunity and lysosomal exocytosis. Genes & development 56 29950492
2019 The ALS-FTD-linked gene product, C9orf72, regulates neuronal morphogenesis via autophagy. Autophagy 55 30669939
2019 ADAR2 mislocalization and widespread RNA editing aberrations in C9orf72-mediated ALS/FTD. Acta neuropathologica 55 30945056
2016 C9ORF72 is a GDP/GTP exchange factor for Rab8 and Rab39 and regulates autophagy. Small GTPases 55 27494456
2017 Unraveling the Role of RNA Mediated Toxicity of C9orf72 Repeats in C9-FTD/ALS. Frontiers in neuroscience 52 29326544
2019 Molecular Mechanisms of Neurodegeneration Related to C9orf72 Hexanucleotide Repeat Expansion. Behavioural neurology 50 30774737
2017 C9orf72: At the intersection of lysosome cell biology and neurodegenerative disease. Traffic (Copenhagen, Denmark) 49 28266105
2014 The C9ORF72 expansion mutation: gene structure, phenotypic and diagnostic issues. Acta neuropathologica 48 24515836
2019 C9orf72 and smcr8 mutant mice reveal MTORC1 activation due to impaired lysosomal degradation and exocytosis. Autophagy 45 31847700
2017 Genetic models of C9orf72: what is toxic? Current opinion in genetics & development 45 28364657
2017 The Enigmatic Role of C9ORF72 in Autophagy. Frontiers in neuroscience 44 28824365
2016 Reduced hnRNPA3 increases C9orf72 repeat RNA levels and dipeptide-repeat protein deposition. EMBO reports 44 27461252
2023 Disrupted myelin lipid metabolism differentiates frontotemporal dementia caused by GRN and C9orf72 gene mutations. Acta neuropathologica communications 43 36967384
2019 Nuclear RNA foci from C9ORF72 expansion mutation form paraspeckle-like bodies. Journal of cell science 43 30745340
2018 Insights into C9ORF72-Related ALS/FTD from Drosophila and iPSC Models. Trends in neurosciences 43 29729808
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
2020 C9orf72 associates with inactive Rag GTPases and regulates mTORC1-mediated autophagosomal and lysosomal biogenesis. Aging cell 40 32100453
2014 Unconventional features of C9ORF72 expanded repeat in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Neurobiology of aging 40 24836899
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 39 30037833
2021 The RNA helicase DHX36-G4R1 modulates C9orf72 GGGGCC hexanucleotide repeat-associated translation. The Journal of biological chemistry 38 34174288
2020 RNA-mediated toxicity in C9orf72 ALS and FTD. Neurobiology of disease 37 32829028
2022 Expanding Clinical Spectrum of C9ORF72-Related Disorders and Promising Therapeutic Strategies: A Review. Neurology. Genetics 36 35620137
2018 The Genetics of C9orf72 Expansions. Cold Spring Harbor perspectives in medicine 36 28130313
2024 Neuromuscular organoids model spinal neuromuscular pathologies in C9orf72 amyotrophic lateral sclerosis. Cell reports 35 38431841
2013 Modelling C9ORF72 hexanucleotide repeat expansion in amyotrophic lateral sclerosis and frontotemporal dementia. Acta neuropathologica 34 24366528
2018 Gray matter changes in asymptomatic C9orf72 and GRN mutation carriers. NeuroImage. Clinical 33 29845007
2017 RNA Misprocessing in C9orf72-Linked Neurodegeneration. Frontiers in cellular neuroscience 32 28744202
2016 Development of Therapeutics for C9ORF72 ALS/FTD-Related Disorders. Molecular neurobiology 31 27349438
2015 C9ORF72 expression and cellular localization over mouse development. Acta neuropathologica communications 31 26408000
2022 C9orf72 functions in the nucleus to regulate DNA damage repair. Cell death and differentiation 30 36220889
2021 C9orf72-derived arginine-rich poly-dipeptides impede phase modifiers. Nature communications 30 34489423
2017 Disease progression in C9orf72 mutation carriers. Neurology 30 28615433
2022 An interaction between synapsin and C9orf72 regulates excitatory synapses and is impaired in ALS/FTD. Acta neuropathologica 29 35876881
2025 Amyotrophic lateral sclerosis caused by hexanucleotide repeat expansions in C9orf72: from genetics to therapeutics. The Lancet. Neurology 28 39986312
2024 Disruption of nuclear speckle integrity dysregulates RNA splicing in C9ORF72-FTD/ALS. Neuron 27 39181135
2021 FDG-PET in presymptomatic C9orf72 mutation carriers. NeuroImage. Clinical 27 34049163
2016 Recognition of c9orf72 Mutant RNA by Single-Stranded Silencing RNAs. Nucleic acid therapeutics 27 28005462
2016 C9orf72's Interaction with Rab GTPases-Modulation of Membrane Traffic and Autophagy. Frontiers in cellular neuroscience 26 27774051
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
2013 C9ORF72 mutations in neurodegenerative diseases. Molecular neurobiology 25 23934648
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
2023 Roadmap for C9ORF72 in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis: Report on the C9ORF72 FTD/ALS Summit. Neurology and therapy 24 37847372
2021 Altered Phase Separation and Cellular Impact in C9orf72-Linked ALS/FTD. Frontiers in cellular neuroscience 24 33967699
2019 Links Between the C9orf72 Repeat Expansion and Psychiatric Symptoms. Current neurology and neuroscience reports 24 31773397
2020 RNA dependent suppression of C9orf72 ALS/FTD associated neurodegeneration by Matrin-3. Acta neuropathologica communications 23 33129345
2014 Biomarker development for C9orf72 repeat expansion in ALS. Brain research 23 25261695
2022 HNRNPK alleviates RNA toxicity by counteracting DNA damage in C9orf72 ALS. Acta neuropathologica 22 35895140
2021 Early life involvement in C9orf72 repeat expansion carriers. Journal of neurology, neurosurgery, and psychiatry 21 33906932
2019 Increased prevalence of granulovacuolar degeneration in C9orf72 mutation. Acta neuropathologica 20 31144027
2014 C9ORF72 hexanucleotide repeats in behavioral and motor neuron disease: clinical heterogeneity and pathological diversity. American journal of neurodegenerative disease 20 24753999
2020 Ablation of C9orf72 together with excitotoxicity induces ALS in rats. The FEBS journal 19 32745320
2019 C9ORF72 protein function and immune dysregulation in amyotrophic lateral sclerosis. Neuroscience letters 19 31568865
2013 RANTing about C9orf72. Neuron 19 23439112
2023 DNA-initiated epigenetic cascades driven by C9orf72 hexanucleotide repeat. Neuron 18 36822200
2023 C9ORF72 suppresses JAK-STAT mediated inflammation. iScience 18 37250330
2013 The clinical and pathological phenotypes of frontotemporal dementia with C9ORF72 mutations. Journal of the neurological sciences 18 24090760
2020 C9orf72-associated SMCR8 protein binds in the ubiquitin pathway and with proteins linked with neurological disease. Acta neuropathologica communications 16 32678027

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