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A serum microRNA sequence reveals fragile X protein pathology in amyotrophic lateral sclerosis

Knowledge about converging disease mechanisms in the heterogeneous syndrome amyotrophic lateral sclerosis (ALS) is rare, but may lead to therapies effective in most ALS cases. Previously, we identified serum microRNAs downregulated in familial ALS, the majority of sporadic ALS patients, but also in...

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Main Authors: Freischmidt, Axel (Author) , Goswami, Anand (Author) , Limm, Katharina (Author) , Zimyanin, Vitaly L (Author) , Demestre, Maria (Author) , Glaß, Hannes (Author) , Holzmann, Karlheinz (Author) , Helferich, Anika Marie (Author) , Brockmann, Sarah J. (Author) , Tripathi, Priyanka (Author) , Yamoah, Alfred (Author) , Poser, Ina (Author) , Oefner, Peter J (Author) , Böckers, Tobias M (Author) , Aronica, Eleonora (Author) , Ludolph, Albert C. (Author) , Andersen, Peter M (Author) , Hermann, Andreas (Author) , Weis, Joachim (Author) , Reinders, Jörg (Author) , Danzer, Karin M (Author) , Weishaupt, Jochen H. (Author)
Format: Article (Journal)
Language:English
Published: 19 April 2021
In: Brain
Year: 2021, Volume: 144, Issue: 4, Pages: 1214-1229
ISSN:1460-2156
DOI:10.1093/brain/awab018
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1093/brain/awab018
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Author Notes:Axel Freischmidt, Anand Goswami, Katharina Limm, Vitaly L. Zimyanin, Maria Demestre, Hannes Glaß, Karlheinz Holzmann, Anika M. Helferich, Sarah J. Brockmann, Priyanka Tripathi, Alfred Yamoah, Ina Poser, Peter J. Oefner, Tobias M. Böckers, Eleonora Aronica, Albert C. Ludolph, Peter M. Andersen, Andreas Hermann, Joachim Weis, Jörg Reinders, Karin M. Danzer and Jochen H. Weishaupt
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Summary:Knowledge about converging disease mechanisms in the heterogeneous syndrome amyotrophic lateral sclerosis (ALS) is rare, but may lead to therapies effective in most ALS cases. Previously, we identified serum microRNAs downregulated in familial ALS, the majority of sporadic ALS patients, but also in presymptomatic mutation carriers. A 5-nucleotide sequence motif (GDCGG; D = G, A or U) was strongly enriched in these ALS-related microRNAs. We hypothesized that deregulation of protein(s) binding predominantly to this consensus motif was responsible for the ALS-linked microRNA fingerprint. Using microRNA pull-down assays combined with mass spectrometry followed by extensive biochemical validation, all members of the fragile X protein family, FMR1, FXR1 and FXR2, were identified to directly and predominantly interact with GDCGG microRNAs through their structurally disordered RGG/RG domains. Preferential association of this protein family with ALS-related microRNAs was confirmed by in vitro binding studies on a transcriptome-wide scale. Immunohistochemistry of lumbar spinal cord revealed aberrant expression level and aggregation of FXR1 and FXR2 in C9orf72- and FUS-linked familial ALS, but also patients with sporadic ALS. Further analysis of ALS autopsies and induced pluripotent stem cell-derived motor neurons with FUS mutations showed co-aggregation of FXR1 with FUS. Hence, our translational approach was able to take advantage of blood microRNAs to reveal CNS pathology, and suggests an involvement of the fragile X-related proteins in familial and sporadic ALS already at a presymptomatic stage. The findings may uncover disease mechanisms relevant to many patients with ALS. They furthermore underscore the systemic, extra-CNS aspect of ALS.
Item Description:Gesehen am 26.07.2021
Physical Description:Online Resource
ISSN:1460-2156
DOI:10.1093/brain/awab018

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