Journal Article

DZNE-2020-01337

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Congenic expression of poly-GA but not poly-PR in mice triggers selective neuron loss and interferon responses found in C9orf72 ALS.

LaClair, K. D. (First author)DZNE* ; Zhou, Q.DZNE* ; Michaelsen, M.DZNE* ; Wefers, B.DZNE* ; Brill, M. S.DZNE* ; Janjic, A. ; Rathkolb, B. ; Farny, D.DZNE* ; Cygan, M.DZNE* ; de Angelis, M. H. ; Wurst, W.DZNE* ; Neumann, M.DZNE* ; Enard, W. ; Misgeld, T.DZNE* ; Arzberger, T.DZNE* ; Edbauer, D. (Last author)DZNE*

2020
Springer Heidelberg

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Please use a persistent id in citations: doi:10.1007/s00401-020-02176-0

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.

Keyword(s): Amyotrophic Lateral Sclerosis: genetics (MeSH) ; Amyotrophic Lateral Sclerosis: immunology (MeSH) ; Amyotrophic Lateral Sclerosis: pathology (MeSH) ; Animals (MeSH) ; C9orf72 Protein: genetics (MeSH) ; DNA Repeat Expansion: genetics (MeSH) ; Disease Models, Animal (MeSH) ; Interferons: biosynthesis (MeSH) ; Mice (MeSH) ; Mice, Transgenic (MeSH) ; Nerve Degeneration: genetics (MeSH) ; Nerve Degeneration: immunology (MeSH) ; Nerve Degeneration: pathology (MeSH) ; Neurons: pathology (MeSH)

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Contributing Institute(s):

1. Cell Biology of Neurodegeneration (AG Edbauer)
2. Genome Engineering (AG Wurst)
3. Interventional Trials and Biomarkers in Neurodegenerative Diseases (AG Heneka1 ; AG Heneka 1)
4. Molecular Neuropathology of Neurodegenerative Diseases (AG Neumann)
5. Neuronal Cell Biology (AG Misgeld)
6. Neuropathology / Brainbank (Neuropathology / Brainbank)
7. Adaptive Immunity in Neurodegeneration (AG Zhou)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)
2. 344 - Clinical and Health Care Research (POF3-344) (POF3-344)
3. 341 - Molecular Signaling (POF3-341) (POF3-341)

Appears in the scientific report 2020

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Springer ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 15 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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