Helferich, Anika M. and Brockmann, Sarah J. and Reinders, Joerg and Deshpande, Dhruva and Holzmann, Karlheinz and Brenner, David and Andersen, Peter M. and Petri, Susanne and Thal, Dietmar R. and Michaelis, Jens and Otto, Markus and Just, Steffen and Ludolph, Albert C. and Danzer, Karin M. and Freischmidt, Axel and Weishaupt, Jochen H. (2018) Dysregulation of a novel miR-1825/TBCB/TUBA4A pathway in sporadic and familial ALS. CELLULAR AND MOLECULAR LIFE SCIENCES, 75 (23). pp. 4301-4319. ISSN 1420-682X, 1420-9071
Full text not available from this repository. (Request a copy)Abstract
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 Type: | Article |
|---|---|
| Uncontrolled Keywords: | AMYOTROPHIC-LATERAL-SCLEROSIS; PROGRESSIVE MOTOR NEURONOPATHY; HEAVY NEUROFILAMENT SUBUNIT; NUCLEOCYTOPLASMIC TRANSPORT; COFACTOR-B; ALPHA-TUBULIN; CELL-DEATH; PROFILIN 1; MUTATIONS; MICRORNAS; Amyotrophic lateral sclerosis; Frontotemporal dementia; MicroRNA; TBCE; Microtubules; Zebrafish |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Institut für Funktionelle Genomik > Lehrstuhl für Funktionelle Genomik (Prof. Oefner) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 04 Oct 2019 09:57 |
| Last Modified: | 04 Oct 2019 09:57 |
| URI: | https://pred.uni-regensburg.de/id/eprint/13434 |
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