Dysregulation of a novel miR-1825/TBCB/TUBA4A pathway in sporadic and familial ALS.
Anika M HelferichSarah J BrockmannJörg ReindersDhruva DeshpandeKarlheinz HolzmannDavid BrennerPeter M AndersenSusanne PetriDietmar R ThalJens MichaelisMarkus OttoSteffen JustAlbert C LudolphKarin M DanzerAxel FreischmidtJochen H WeishauptPublished in: Cellular and molecular life sciences : CMLS (2018)
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.
Keyphrases
- amyotrophic lateral sclerosis
- end stage renal disease
- cell proliferation
- newly diagnosed
- ejection fraction
- healthcare
- prognostic factors
- chronic kidney disease
- genome wide
- gene expression
- long non coding rna
- copy number
- late onset
- blood brain barrier
- early onset
- patient reported outcomes
- single molecule
- multiple sclerosis
- optical coherence tomography
- molecular dynamics simulations
- protein protein
- long noncoding rna