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 (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.

Brockmann, Sarah J. (author)
Reinders, Jörg (author)
Deshpande, Dhruva (author)
Holzmann, Karlheinz (author)
Brenner, David (author)
Andersen, Peter M.,1962-Umeå universitet,Klinisk neurovetenskap,Department of Neurology, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany(Swepub:umu)pean0001 (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)
Umeå universitetKlinisk neurovetenskap (creator_code:org_t)

In:Cellular and Molecular Life Sciences (CMLS): Springer75:23, s. 4301-43191420-682X1420-9071

By the author/editor: Helferich, Anika ...; Brockmann, Sarah ...; Reinders, Jörg; Deshpande, Dhruv ...; Holzmann, Karlhe ...; Brenner, David; show more...; Andersen, Peter ...; Petri, Susanne; Thal, Dietmar R.; Michaelis, Jens; Otto, Markus; Just, Steffen; Ludolph, Albert ...; Danzer, Karin M.; Freischmidt, Axe ...; Weishaupt, Joche ...; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Medical Biotechn ...; and Medical Biotechn ...

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