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000153340 0247_ $$2doi$$a10.1007/s00401-020-02176-0
000153340 0247_ $$2pmid$$apmid:32562018
000153340 0247_ $$2pmc$$apmc:PMC7360660
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000153340 0247_ $$2ISSN$$a1432-0533
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000153340 037__ $$aDZNE-2020-01337
000153340 041__ $$aEnglish
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000153340 1001_ $$0P:(DE-2719)2811939$$aLaClair, Katherine D$$b0$$eFirst author$$udzne
000153340 245__ $$aCongenic expression of poly-GA but not poly-PR in mice triggers selective neuron loss and interferon responses found in C9orf72 ALS.
000153340 260__ $$aHeidelberg$$bSpringer$$c2020
000153340 3367_ $$2DRIVER$$aarticle
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000153340 520__ $$aExpansion 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.
000153340 536__ $$0G:(DE-HGF)POF3-342$$a342 - Disease Mechanisms and Model Systems (POF3-342)$$cPOF3-342$$fPOF III$$x0
000153340 536__ $$0G:(DE-HGF)POF3-344$$a344 - Clinical and Health Care Research (POF3-344)$$cPOF3-344$$fPOF III$$x1
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000153340 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: genetics
000153340 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: immunology
000153340 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: pathology
000153340 650_2 $$2MeSH$$aAnimals
000153340 650_2 $$2MeSH$$aC9orf72 Protein: genetics
000153340 650_2 $$2MeSH$$aDNA Repeat Expansion: genetics
000153340 650_2 $$2MeSH$$aDisease Models, Animal
000153340 650_2 $$2MeSH$$aInterferons: biosynthesis
000153340 650_2 $$2MeSH$$aMice
000153340 650_2 $$2MeSH$$aMice, Transgenic
000153340 650_2 $$2MeSH$$aNerve Degeneration: genetics
000153340 650_2 $$2MeSH$$aNerve Degeneration: immunology
000153340 650_2 $$2MeSH$$aNerve Degeneration: pathology
000153340 650_2 $$2MeSH$$aNeurons: pathology
000153340 7001_ $$0P:(DE-2719)2811347$$aZhou, Qihui$$b1$$udzne
000153340 7001_ $$0P:(DE-2719)2811691$$aMichaelsen, Meike$$b2$$udzne
000153340 7001_ $$0P:(DE-2719)2810988$$aWefers, Benedikt$$b3$$udzne
000153340 7001_ $$0P:(DE-2719)9000978$$aBrill, Monika S$$b4$$udzne
000153340 7001_ $$0P:(DE-HGF)0$$aJanjic, Aleksandar$$b5
000153340 7001_ $$0P:(DE-HGF)0$$aRathkolb, Birgit$$b6
000153340 7001_ $$0P:(DE-2719)2812127$$aFarny, Daniel$$b7$$udzne
000153340 7001_ $$0P:(DE-2719)9000520$$aCygan, Mikolaj$$b8$$udzne
000153340 7001_ $$0P:(DE-HGF)0$$ade Angelis, Martin Hrabe$$b9
000153340 7001_ $$0P:(DE-2719)2000028$$aWurst, Wolfgang$$b10$$udzne
000153340 7001_ $$0P:(DE-2719)2810592$$aNeumann, Manuela$$b11$$udzne
000153340 7001_ $$0P:(DE-HGF)0$$aEnard, Wolfgang$$b12
000153340 7001_ $$0P:(DE-2719)2810727$$aMisgeld, Thomas$$b13$$udzne
000153340 7001_ $$0P:(DE-2719)2811333$$aArzberger, Thomas$$b14$$udzne
000153340 7001_ $$0P:(DE-2719)2231621$$aEdbauer, Dieter$$b15$$eLast author$$udzne
000153340 773__ $$0PERI:(DE-600)1458410-4$$a10.1007/s00401-020-02176-0$$gVol. 140, no. 2, p. 121 - 142$$n2$$p121 - 142$$tActa neuropathologica$$v140$$x1432-0533$$y2020
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