ZFIN ID: ZDB-PUB-180722-20
Dysregulation of a novel miR-1825/TBCB/TUBA4A pathway in sporadic and familial ALS
Helferich, A.M., Brockmann, S.J., Reinders, J., Deshpande, D., Holzmann, K., Brenner, D., Andersen, P.M., Petri, S., Thal, D.R., Michaelis, J., Otto, M., Just, S., Ludolph, A.C., Danzer, K.M., Freischmidt, A., Weishaupt, J.H.
Date: 2018
Source: Cellular and molecular life sciences : CMLS   75(23): 4301-4319 (Journal)
Registered Authors: Just, Steffen
Keywords: Amyotrophic lateral sclerosis, Frontotemporal dementia, MicroRNA, Microtubules, TBCE, Zebrafish
MeSH Terms:
  • Aged
  • Amyotrophic Lateral Sclerosis/genetics*
  • Amyotrophic Lateral Sclerosis/metabolism
  • Amyotrophic Lateral Sclerosis/pathology
  • Animals
  • Brain/metabolism
  • Brain/pathology
  • Cells, Cultured
  • Female
  • Gene Expression Profiling*
  • Genetic Predisposition to Disease/genetics*
  • HEK293 Cells
  • Humans
  • Male
  • Mice, Inbred C57BL
  • MicroRNAs/genetics*
  • Microtubule-Associated Proteins/genetics*
  • Microtubule-Associated Proteins/metabolism
  • Middle Aged
  • Tubulin/genetics*
  • Tubulin/metabolism
PubMed: 30030593 Full text @ Cell. Mol. Life Sci.
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.