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A serum microRNA se...
A serum microRNA sequence reveals fragile X protein pathology in amyotrophic lateral sclerosis
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- Freischmidt, Axel (author)
- Department of Neurology, Ulm University, Ulm, Germany; German Center For Neurodegenerative Diseases (DZNE) Ulm, Ulm, Germany
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- Goswami, Anand (author)
- Institute of Neuropathology, RWTH Aachen University Hospital, Aachen, Germany
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- Limm, Katharina (author)
- Institute of Functional Genomics, University of Regensburg, Regensburg, Germany
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- Zimyanin, Vitaly L. (author)
- Department of Neurology, Technical University Dresden, Dresden, Germany; Department of Biology, University of Virginia, VA, Charlottesville, United States
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- Demestre, Maria (author)
- Institute for Anatomy and Cell Biology, Ulm University, Ulm, Germany
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- Glaß, Hannes (author)
- Translational Neurodegeneration Section "Albrecht-Kossel", Department of Neurology, University Medical Center Rostock, University of Rostock, Rostock, Germany
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- Holzmann, Karlheinz (author)
- Core Unit Genomics, Ulm University, Ulm, Germany
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- Helferich, Anika M. (author)
- Department of Neurology, Ulm University, Ulm, Germany
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- Brockmann, Sarah J. (author)
- Department of Neurology, Ulm University, Ulm, Germany
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- Tripathi, Priyanka (author)
- Institute of Neuropathology, RWTH Aachen University Hospital, Aachen, Germany
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- Yamoah, Alfred (author)
- Institute of Neuropathology, RWTH Aachen University Hospital, Aachen, Germany
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- Poser, Ina (author)
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
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- Oefner, Peter J. (author)
- Institute of Functional Genomics, University of Regensburg, Regensburg, Germany
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- Böckers, Tobias M. (author)
- German Center For Neurodegenerative Diseases (DZNE) Ulm, Ulm, Germany; Institute for Anatomy and Cell Biology, Ulm University, Ulm, Germany
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- Aronica, Eleonora (author)
- University of Amsterdam, Department of (Neuro)Pathology, Amsterdam Neuroscience, Amsterdam, Netherlands
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- Ludolph, Albert C. (author)
- Department of Neurology, Ulm University, Ulm, Germany; German Center For Neurodegenerative Diseases (DZNE) Ulm, Ulm, Germany
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- Andersen, Peter M., 1962- (author)
- Umeå universitet,Neurovetenskaper
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- Hermann, Andreas (author)
- 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
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- Weis, Joachim (author)
- Institute of Neuropathology, RWTH Aachen University Hospital, Aachen, Germany
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- Reinders, Jörg (author)
- Institute of Functional Genomics, University of Regensburg, Regensburg, Germany
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- Danzer, Karin M. (author)
- Department of Neurology, Ulm University, Ulm, Germany
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- Weishaupt, Jochen H. (author)
- 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
- English.
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In: Brain. - : Oxford University Press. - 0006-8950 .- 1460-2156. ; 144:4, s. 1214-1229
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Abstract
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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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Neurologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Neurology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
Keyword
- amyotrophic lateral sclerosis
- FMR1/FMRP
- FXR1
- FXR2
- miRNA
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Freischmidt, Axe ...
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Goswami, Anand
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Limm, Katharina
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Zimyanin, Vitaly ...
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Demestre, Maria
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Glaß, Hannes
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Holzmann, Karlhe ...
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Helferich, Anika ...
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Brockmann, Sarah ...
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Tripathi, Priyan ...
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Yamoah, Alfred
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Poser, Ina
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Oefner, Peter J.
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Böckers, Tobias ...
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Aronica, Eleonor ...
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Ludolph, Albert ...
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Andersen, Peter ...
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Hermann, Andreas
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Weis, Joachim
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Reinders, Jörg
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Danzer, Karin M.
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Weishaupt, Joche ...
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Umeå University