Home > Publications Database > Congenic expression of poly-GA but not poly-PR in mice triggers selective neuron loss and interferon responses found in C9orf72 ALS. > print

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024 7 _ |a 10.1007/s00401-020-02176-0
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024 7 _ |a pmc:PMC7360660
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024 7 _ |a 1432-0533
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037 _ _ |a DZNE-2020-01337
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a LaClair, Katherine D
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245 _ _ |a Congenic expression of poly-GA but not poly-PR in mice triggers selective neuron loss and interferon responses found in C9orf72 ALS.
260 _ _ |a Heidelberg
|c 2020
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520 _ _ |a 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.
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650 _ 2 |a Amyotrophic Lateral Sclerosis: genetics
|2 MeSH
650 _ 2 |a Amyotrophic Lateral Sclerosis: immunology
|2 MeSH
650 _ 2 |a Amyotrophic Lateral Sclerosis: pathology
|2 MeSH
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a C9orf72 Protein: genetics
|2 MeSH
650 _ 2 |a DNA Repeat Expansion: genetics
|2 MeSH
650 _ 2 |a Disease Models, Animal
|2 MeSH
650 _ 2 |a Interferons: biosynthesis
|2 MeSH
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a Mice, Transgenic
|2 MeSH
650 _ 2 |a Nerve Degeneration: genetics
|2 MeSH
650 _ 2 |a Nerve Degeneration: immunology
|2 MeSH
650 _ 2 |a Nerve Degeneration: pathology
|2 MeSH
650 _ 2 |a Neurons: pathology
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700 1 _ |a Zhou, Qihui
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700 1 _ |a Michaelsen, Meike
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700 1 _ |a Wefers, Benedikt
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700 1 _ |a Brill, Monika S
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700 1 _ |a Janjic, Aleksandar
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700 1 _ |a Rathkolb, Birgit
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700 1 _ |a Farny, Daniel
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700 1 _ |a Cygan, Mikolaj
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700 1 _ |a de Angelis, Martin Hrabe
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700 1 _ |a Wurst, Wolfgang
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700 1 _ |a Misgeld, Thomas
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700 1 _ |a Arzberger, Thomas
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700 1 _ |a Edbauer, Dieter
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773 _ _ |a 10.1007/s00401-020-02176-0
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