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Dysregulation of a novel miR-1825/TBCB/TUBA4A pathway in sporadic and familial ALS

Genetic and functional studies suggest diverse pathways being affected in the neurodegenerative disease amyotrophic lateral sclerosis (ALS), while knowledge about converging disease mechanisms is rare. We detected a downregulation of microRNA-1825 in CNS and extra-CNS system organs of both sporadic...

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Main Authors: Helferich, Anika Marie (Author) , Brockmann, Sarah J. (Author) , Reinders, Jörg (Author) , Deshpande, Dhruva (Author) , Holzmann, Karlheinz (Author) , Brenner, David (Author) , Andersen, Peter M. (Author) , Petri, Susanne (Author) , Thal, Dietmar R. (Author) , Michaelis, Jens (Author) , Otto, Markus (Author) , Just, Steffen (Author) , Ludolph, Albert C. (Author) , Danzer, Karin M. (Author) , Freischmidt, Axel (Author) , Weishaupt, Jochen H. (Author)
Format: Article (Journal)
Language:English
Published: 20 July 2018
In: Cellular and molecular life sciences
Year: 2018, Volume: 75, Issue: 23, Pages: 4301-4319
ISSN:1420-9071
DOI:10.1007/s00018-018-2873-1
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1007/s00018-018-2873-1
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Author Notes:Anika M. Helferich, Sarah J. Brockmann, Jörg Reinders, Dhruva Deshpande, Karlheinz Holzmann, David Brenner, Peter M. Andersen, Susanne Petri, Dietmar R. Thal, Jens Michaelis, Markus Otto, Steffen Just, Albert C. Ludolph, Karin M. Danzer, Axel Freischmidt, Jochen H. Weishaupt
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Summary:Genetic and functional studies suggest diverse pathways being affected in the neurodegenerative disease amyotrophic lateral sclerosis (ALS), while knowledge about converging disease mechanisms is rare. We detected a downregulation of microRNA-1825 in CNS and extra-CNS system organs of both sporadic (sALS) and familial ALS (fALS) patients. Combined transcriptomic and proteomic analysis revealed that reduced levels of microRNA-1825 caused a translational upregulation of tubulin-folding cofactor b (TBCB). Moreover, we found that excess TBCB led to depolymerization and degradation of tubulin alpha-4A (TUBA4A), which is encoded by a known ALS gene. Importantly, the increase in TBCB and reduction of TUBA4A protein was confirmed in brain cortex tissue of fALS and sALS patients, and led to motor axon defects in an in vivo model. Our discovery of a microRNA-1825/TBCB/TUBA4A pathway reveals a putative pathogenic cascade in both fALS and sALS extending the relevance of TUBA4A to a large proportion of ALS cases.
Item Description:Gesehen am 08.07.2021
Physical Description:Online Resource
ISSN:1420-9071
DOI:10.1007/s00018-018-2873-1

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