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

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

Freischmidt, Axel (författare): Department of Neurology, Ulm University, Ulm, Germany; German Center For Neurodegenerative Diseases (DZNE) Ulm, Ulm, Germany

Goswami, Anand (författare): Institute of Neuropathology, RWTH Aachen University Hospital, Aachen, Germany

Limm, Katharina (författare): Institute of Functional Genomics, University of Regensburg, Regensburg, Germany

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Zimyanin, Vitaly L. (författare): Department of Neurology, Technical University Dresden, Dresden, Germany; Department of Biology, University of Virginia, VA, Charlottesville, United States

Demestre, Maria (författare): Institute for Anatomy and Cell Biology, Ulm University, Ulm, Germany

Glaß, Hannes (författare): Translational Neurodegeneration Section "Albrecht-Kossel", Department of Neurology, University Medical Center Rostock, University of Rostock, Rostock, Germany

Holzmann, Karlheinz (författare): Core Unit Genomics, Ulm University, Ulm, Germany

Helferich, Anika M. (författare): Department of Neurology, Ulm University, Ulm, Germany

Brockmann, Sarah J. (författare): Department of Neurology, Ulm University, Ulm, Germany

Tripathi, Priyanka (författare): Institute of Neuropathology, RWTH Aachen University Hospital, Aachen, Germany

Yamoah, Alfred (författare): Institute of Neuropathology, RWTH Aachen University Hospital, Aachen, Germany

Poser, Ina (författare): Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany

Oefner, Peter J. (författare): Institute of Functional Genomics, University of Regensburg, Regensburg, Germany

Böckers, Tobias M. (författare): German Center For Neurodegenerative Diseases (DZNE) Ulm, Ulm, Germany; Institute for Anatomy and Cell Biology, Ulm University, Ulm, Germany

Aronica, Eleonora (författare): University of Amsterdam, Department of (Neuro)Pathology, Amsterdam Neuroscience, Amsterdam, Netherlands

Ludolph, Albert C. (författare): Department of Neurology, Ulm University, Ulm, Germany; German Center For Neurodegenerative Diseases (DZNE) Ulm, Ulm, Germany

Andersen, Peter M., 1962- (författare): Umeå universitet,Neurovetenskaper

Hermann, Andreas (författare): Department of Neurology, Technical University Dresden, Dresden, Germany; Translational Neurodegeneration Section "Albrecht-Kossel", Department of Neurology, University Medical Center Rostock, University of Rostock, Rostock, Germany; Center for Transdisciplinary Neurosciences Rostock (CTNR), University Medical Center Rostock, University of Rostock, Rostock, Germany; German Center for Neurodegenerative Diseases (DZNE) Rostock/Greifswald, Rostock, Germany

Weis, Joachim (författare): Institute of Neuropathology, RWTH Aachen University Hospital, Aachen, Germany

Reinders, Jörg (författare): Institute of Functional Genomics, University of Regensburg, Regensburg, Germany

Danzer, Karin M. (författare): Department of Neurology, Ulm University, Ulm, Germany

Weishaupt, Jochen H. (författare): Department of Neurology, Ulm University, Ulm, Germany; Division for Neurodegenerative Diseases, Neurology Department, University Medicine Mannheim, Heidelberg University, Mannheim, Germany

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(creator_code:org_t)

2021-04-19
2021
Engelska.
Ingår i: Brain. - : Oxford University Press. - 0006-8950 .- 1460-2156. ; 144:4, s. 1214-1229

Relaterad länk:: https://doi.org/10.1...; visa fler...; https://umu.diva-por... (primary) (Raw object); https://academic.oup...; https://urn.kb.se/re...; https://doi.org/10.1...; visa färre...

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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.

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

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