C9orf72 poly(GR) aggregation induces TDP-43 proteinopathy

Topic: Brain proteins, microglia and lab models

TAR DNA-binding protein 43 (TDP-43) inclusions are a pathological hallmark of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), including cases caused by G 4 C 2 repeat expansions in the C9orf72 gene (c9FTD/ALS). Providing mechanistic insight into the link between C9orf72 mutations and TDP-43 pathology, we demonstrated that a glycine-arginine repeat protein [poly(GR)] translated from expanded G 4 C 2 repeats was sufficient to promote aggregation of endogenous TDP-43. In particular, toxic poly(GR) proteins mediated sequestration of full-length TDP-43 in an RNA-independent manner to induce cytoplasmic TDP-43 inclusion formation. Moreover, in GFP-(GR) 200 mice, poly(GR) caused the mislocalization of nucleocytoplasmic transport factors and nuclear pore complex proteins. These mislocalization events resulted in the aberrant accumulation of endogenous TDP-43 in the cytoplasm where it co-aggregated with poly(GR). Last, we demonstrated that treating G 4 C 2 repeat-expressing mice with repeat-targeting antisense oligonucleotides lowered poly(GR) burden, which was accompanied by reduced TDP-43 pathology and neurodegeneration, including lowering of plasma neurofilament light (NFL) concentration. These results contribute to clarification of the mechanism by which poly(GR) drives TDP-43 proteinopathy, confirm that G 4 C 2 -targeted therapeutics reduce TDP-43 pathology in vivo, and demonstrate that alterations in plasma NFL provide insight into the therapeutic efficacy of disease-modifying treatments.

Key findings

• Providing mechanistic insight into the link between C9orf72 mutations and TDP-43 pathology, we demonstrated that a glycine-arginine repeat protein [poly(GR)] translated from expanded G 4 C 2 repeats was sufficient to promote aggregation of endogenous TDP-43.
• Last, we demonstrated that treating G 4 C 2 repeat-expressing mice with repeat-targeting antisense oligonucleotides lowered poly(GR) burden, which was accompanied by reduced TDP-43 pathology and neurodegeneration, including lowering of plasma neurofilament light (NFL) concentration.
• These results contribute to clarification of the mechanism by which poly(GR) drives TDP-43 proteinopathy, confirm that G 4 C 2 -targeted therapeutics reduce TDP-43 pathology in vivo, and demonstrate that alterations in plasma NFL provide insight into the therapeutic efficacy of disease-modifying treatments.

Why it matters

In mice, a protein called poly(GR) produced from expanded C9orf72 repeats caused TDP-43 to clump in the cytoplasm, and antisense oligonucleotides reduced this pathology and neurodegeneration. These are animal findings and do not yet show a treatment for people with frontotemporal dementia or ALS.

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Study details

• Evidence strengthLow

Read the original

• DOI: 10.1126/scitranslmed.abb3774
• PubMed: 32878979
• Original source →
• Free full text: PubMed Central →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{cook2020-32878979,
  author  = {Cook, C. N. and Wu, Y. and Odeh, H. M. and Gendron, T. F. and Jansen-West, K. and Del Rosso, G. and Yue, M. and Jiang, P. and others},
  title   = {{C9orf72 poly(GR) aggregation induces TDP-43 proteinopathy}},
  journal = {Science translational medicine},
  year    = {2020},
  doi     = {10.1126/scitranslmed.abb3774},
  pmid    = {32878979},
  url     = {https://doi.org/10.1126/scitranslmed.abb3774}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here. Showing 12 of 24.

• A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD Neuron · 2011-09-21 · usefulness score 63/100 · Lewy body dementia
• Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Science (New York, N.Y.) · 2006-10-01 · usefulness score 62/100 · Lewy body dementia
• Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS Neuron · 2011-09-21 · usefulness score 62/100 · Lewy body dementia
• The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS Science (New York, N.Y.) · 2013-02-07 · usefulness score 59/100 · Lewy body dementia
• Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS Nature neuroscience · 2015-09-01 · usefulness score 59/100 · Lewy body dementia
• GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport Nature · 2015-08-26 · usefulness score 58/100 · Lewy body dementia
• C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins Nature neuroscience · 2016-03-21 · usefulness score 58/100 · Brain tissue and pathology
• Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS Neuron · 2013-02-12 · usefulness score 57/100 · Lewy body dementia
• RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia Proceedings of the National Academy of Sciences of the United States of America · 2013-11-18 · usefulness score 57/100 · Lewy body dementia
• Neurodegeneration. C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits Science (New York, N.Y.) · 2015-05-14 · usefulness score 57/100 · Lewy body dementia
• The C9orf72 repeat expansion disrupts nucleocytoplasmic transport Nature · 2015-08-26 · usefulness score 57/100 · Lewy body dementia
• TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Biochemical and biophysical research communications · 2006-10-30 · usefulness score 56/100 · Lewy body dementia

Later studies that cite this one

3 studies in the alzhub library list this one in their references.

• SUMO2/3 conjugation of TDP-43 protects against aggregation Science Advances · 2025-02-21 · usefulness score 52/100 · Brain tissue and pathology
• Molecular Mechanisms of Protein Aggregation in ALS-FTD: Focus on TDP-43 and Cellular Protective Responses Cells · 2025-05-08 · usefulness score 44/100 · Brain tissue and pathology
• Gain-of-function ANXA11 mutation cause late-onset ALS with aberrant protein aggregation, neuroinflammation and autophagy impairment Acta Neuropathologica Communications · 2025-01-04 · usefulness score 43/100 · Brain tissue and pathology

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• Quantitative analysis and clinico-pathological correlations of different dipeptide repeat protein pathologies in C9ORF72 mutation carriers Acta neuropathologica · 2015-09-15 · usefulness score 51/100
• G-quadruplex-binding small molecules ameliorate C9orf72 FTD/ALS pathology in vitro and in vivo EMBO molecular medicine · 2018-01-01 · usefulness score 49/100
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• Differential roles of the ubiquitin proteasome system and autophagy in the clearance of soluble and aggregated TDP-43 species Journal of cell science · 2014-01-14 · usefulness score 51/100 · Brain tissue and pathology
• Chemical and Molecular Strategies in Restoring Autophagic Flux in TDP-43 Proteinopathy Molecules · 2026-03-10 · usefulness score 36/100 · Brain tissue and pathology
• Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in alpha-synuclein models of Parkinson's and Lewy body diseases The Journal of neuroscience : the official journal of the Society for Neuroscience · 2009-10-01 · usefulness score 52/100 · Lewy body dementia

Similar studies

• Aberrant deposition of stress granule-resident proteins linked to C9orf72-associated TDP-43 proteinopathy 2019 · Clinical safety
• TDP-43 is intrinsically aggregation-prone, and amyotrophic lateral sclerosis-linked mutations accelerate aggregation and increase toxicity 2009 · Lewy body dementia
• Seeded aggregation of TDP-43 induces its loss of function and reveals early pathological signatures 2025 · Brain tissue and pathology
• Proteomics and <i>C9orf72</i> neuropathology identify ribosomes as poly-GR/PR interactors driving toxicity 2018 · Clinical safety
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