Dysregulation of a novel miR-1825/TBCB/TUBA4A pathway in sporadic and familial ALS
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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.
KeywordsAmyotrophic lateral sclerosis Frontotemporal dementia MicroRNA TBCE Microtubules Zebrafish
Amyotrophic lateral sclerosis
Chromosome 9 open reading frame 72
Central nervous system
Days in vitro
Tubulin-folding cofactor b
Tubulin-folding cofactor e
Transactive response DNA-binding protein 43
We are indebted to the patients and families participating in this study. We are also grateful to Elena Jasovski, Ramona Bück, Nadine Todt and Aline Sage for their excellent technical assistance. We also thank Lüder-Hinrich Meyer (Ulm University) for providing the dual-luciferase miRNA reporter plasmid and Jasmin Breymayer and Angelika Rück of the core facility confocal and multi-photon microscopy in Ulm for their help and technical advice. This work was supported in whole or in parts by grants from the German Federal Ministry of Education and Research (STRENGTH consortium/BMBF, 01GI0704; German network for ALS research (MND-NET)), the Charcot Foundation for ALS Research (ACL, JHW), and the DFG-funded Swabian ALS Registry.
AMH, SJB, JR, DD, AF and KH performed experiments and analyzed data. AMH, AF and JHW designed and supervised the study and interpreted the results. PMA, SP and DRT provided post-mortem tissue samples. JM, MO, ACL, DB, SJ and KMD helped conducting the study and provided critical input for scientific interpretations. AMH, AF and JHW wrote the manuscript.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
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