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Congenic expression of poly-GA but not poly-PR in mice triggers selective neuron loss and interferon responses found in C9orf72 ALS.
Acta Neuropathol. 2020 Aug; 140(2):121-142.AN

Abstract

Expansion of a (G4C2)n repeat in C9orf72 causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but the link of the five repeat-encoded dipeptide repeat (DPR) proteins to neuroinflammation, TDP-43 pathology, and neurodegeneration is unclear. Poly-PR is most toxic in vitro, but poly-GA is far more abundant in patients. To directly compare these in vivo, we created congenic poly-GA and poly-PR mice. 40% of poly-PR mice were affected with ataxia and seizures, requiring euthanasia by 6 weeks of age. The remaining poly-PR mice were asymptomatic at 14 months of age, likely due to an 80% reduction of the transgene mRNA in this subgroup. In contrast, all poly-GA mice showed selective neuron loss, inflammation, as well as muscle denervation and wasting requiring euthanasia before 7 weeks of age. In-depth analysis of peripheral organs and blood samples suggests that peripheral organ failure does not drive these phenotypes. Although transgene mRNA levels were similar between poly-GA and affected poly-PR mice, poly-GA aggregated far more abundantly than poly-PR in the CNS and was also found in skeletal muscle. In addition, TDP-43 and other disease-linked RNA-binding proteins co-aggregated in rare nuclear inclusions in the hippocampus and frontal cortex only in poly-GA mice. Transcriptome analysis revealed activation of an interferon-responsive pro-inflammatory microglial signature in end-stage poly-GA but not poly-PR mice. This signature was also found in all ALS patients and enriched in C9orf72 cases. In summary, our rigorous comparison of poly-GA and poly-PR toxicity in vivo indicates that poly-GA, but not poly-PR at the same mRNA expression level, promotes interferon responses in C9orf72 disease and contributes to TDP-43 abnormalities and neuron loss selectively in disease-relevant regions.

Authors+Show Affiliations

German Center for Neurodegenerative Diseases (DZNE), Munich, 81377, Munich, Germany.German Center for Neurodegenerative Diseases (DZNE), Munich, 81377, Munich, Germany. Munich Cluster for Systems Neurology (SyNergy), 80336, Munich, Germany.German Center for Neurodegenerative Diseases (DZNE), Munich, 81377, Munich, Germany.German Center for Neurodegenerative Diseases (DZNE), Munich, 81377, Munich, Germany.Munich Cluster for Systems Neurology (SyNergy), 80336, Munich, Germany. Institute of Neuronal Cell Biology, Technische Universität München, 80802, Munich, Germany.Department Biology II, Anthropology and Human Genomics, Ludwig-Maximilians-University Munich, 82152, Martinsried, Germany.German Mouse Clinic, Institute for Experimental Genetics, German Research Center for Environmental Health, Helmholtz Zentrum München, Neuherberg, Germany. Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-University Munich, 81377, Munich, Germany. German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.German Center for Neurodegenerative Diseases (DZNE), Munich, 81377, Munich, Germany.German Center for Neurodegenerative Diseases (DZNE), Munich, 81377, Munich, Germany.German Mouse Clinic, Institute for Experimental Genetics, German Research Center for Environmental Health, Helmholtz Zentrum München, Neuherberg, Germany. German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany. Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, Alte Akademie 8, 85354, Freising, Germany.German Center for Neurodegenerative Diseases (DZNE), Munich, 81377, Munich, Germany. Munich Cluster for Systems Neurology (SyNergy), 80336, Munich, Germany.German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany. Department of Neuropathology, University of Tübingen, Tübingen, Germany.Department Biology II, Anthropology and Human Genomics, Ludwig-Maximilians-University Munich, 82152, Martinsried, Germany.German Center for Neurodegenerative Diseases (DZNE), Munich, 81377, Munich, Germany. Munich Cluster for Systems Neurology (SyNergy), 80336, Munich, Germany. Institute of Neuronal Cell Biology, Technische Universität München, 80802, Munich, Germany.German Center for Neurodegenerative Diseases (DZNE), Munich, 81377, Munich, Germany. Munich Cluster for Systems Neurology (SyNergy), 80336, Munich, Germany. Center for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, 81377, Munich, Germany. Department of Psychiatry and Psychotherapy, University Hospital, Ludwig-Maximilians-University Munich, 80336, Munich, Germany.German Center for Neurodegenerative Diseases (DZNE), Munich, 81377, Munich, Germany. dieter.edbauer@dzne.de. Munich Cluster for Systems Neurology (SyNergy), 80336, Munich, Germany. dieter.edbauer@dzne.de. Graduate School of Systemic Neurosciences (GSN), Ludwig-Maximilians-University Munich, 81377, Munich, Germany. dieter.edbauer@dzne.de.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32562018

Citation

LaClair, Katherine D., et al. "Congenic Expression of poly-GA but Not poly-PR in Mice Triggers Selective Neuron Loss and Interferon Responses Found in C9orf72 ALS." Acta Neuropathologica, vol. 140, no. 2, 2020, pp. 121-142.
LaClair KD, Zhou Q, Michaelsen M, et al. Congenic expression of poly-GA but not poly-PR in mice triggers selective neuron loss and interferon responses found in C9orf72 ALS. Acta Neuropathol. 2020;140(2):121-142.
LaClair, K. D., Zhou, Q., Michaelsen, M., Wefers, B., Brill, M. S., Janjic, A., Rathkolb, B., Farny, D., Cygan, M., de Angelis, M. H., Wurst, W., Neumann, M., Enard, W., Misgeld, T., Arzberger, T., & Edbauer, D. (2020). Congenic expression of poly-GA but not poly-PR in mice triggers selective neuron loss and interferon responses found in C9orf72 ALS. Acta Neuropathologica, 140(2), 121-142. https://doi.org/10.1007/s00401-020-02176-0
LaClair KD, et al. Congenic Expression of poly-GA but Not poly-PR in Mice Triggers Selective Neuron Loss and Interferon Responses Found in C9orf72 ALS. Acta Neuropathol. 2020;140(2):121-142. PubMed PMID: 32562018.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Congenic expression of poly-GA but not poly-PR in mice triggers selective neuron loss and interferon responses found in C9orf72 ALS. AU - LaClair,Katherine D, AU - Zhou,Qihui, AU - Michaelsen,Meike, AU - Wefers,Benedikt, AU - Brill,Monika S, AU - Janjic,Aleksandar, AU - Rathkolb,Birgit, AU - Farny,Daniel, AU - Cygan,Mikolaj, AU - de Angelis,Martin Hrabe, AU - Wurst,Wolfgang, AU - Neumann,Manuela, AU - Enard,Wolfgang, AU - Misgeld,Thomas, AU - Arzberger,Thomas, AU - Edbauer,Dieter, Y1 - 2020/06/19/ PY - 2020/04/22/received PY - 2020/06/04/accepted PY - 2020/06/04/revised PY - 2020/6/21/pubmed PY - 2020/6/21/medline PY - 2020/6/21/entrez KW - ALS KW - C9orf72 KW - FTD KW - Interferon KW - Microglia KW - Mouse model KW - Neurodegeneration SP - 121 EP - 142 JF - Acta neuropathologica JO - Acta Neuropathol. VL - 140 IS - 2 N2 - Expansion of a (G4C2)n repeat in C9orf72 causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but the link of the five repeat-encoded dipeptide repeat (DPR) proteins to neuroinflammation, TDP-43 pathology, and neurodegeneration is unclear. Poly-PR is most toxic in vitro, but poly-GA is far more abundant in patients. To directly compare these in vivo, we created congenic poly-GA and poly-PR mice. 40% of poly-PR mice were affected with ataxia and seizures, requiring euthanasia by 6 weeks of age. The remaining poly-PR mice were asymptomatic at 14 months of age, likely due to an 80% reduction of the transgene mRNA in this subgroup. In contrast, all poly-GA mice showed selective neuron loss, inflammation, as well as muscle denervation and wasting requiring euthanasia before 7 weeks of age. In-depth analysis of peripheral organs and blood samples suggests that peripheral organ failure does not drive these phenotypes. Although transgene mRNA levels were similar between poly-GA and affected poly-PR mice, poly-GA aggregated far more abundantly than poly-PR in the CNS and was also found in skeletal muscle. In addition, TDP-43 and other disease-linked RNA-binding proteins co-aggregated in rare nuclear inclusions in the hippocampus and frontal cortex only in poly-GA mice. Transcriptome analysis revealed activation of an interferon-responsive pro-inflammatory microglial signature in end-stage poly-GA but not poly-PR mice. This signature was also found in all ALS patients and enriched in C9orf72 cases. In summary, our rigorous comparison of poly-GA and poly-PR toxicity in vivo indicates that poly-GA, but not poly-PR at the same mRNA expression level, promotes interferon responses in C9orf72 disease and contributes to TDP-43 abnormalities and neuron loss selectively in disease-relevant regions. SN - 1432-0533 UR - https://www.unboundmedicine.com/medline/citation/32562018/Congenic_expression_of_poly-GA_but_not_poly-PR_in_mice_triggers_selective_neuron_loss_and_interferon_responses_found_in_C9orf72_ALS L2 - https://dx.doi.org/10.1007/s00401-020-02176-0 DB - PRIME DP - Unbound Medicine ER -
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