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Cell Mol Life Sci. 2018 Dec;75(23):4301-4319. doi: 10.1007/s00018-018-2873-1. Epub 2018 Jul 20.

Dysregulation of a novel miR-1825/TBCB/TUBA4A pathway in sporadic and familial ALS.

Author information

1
Department of Neurology, Ulm University, Albert-Einstein-Allee 11, 89081, Ulm, Germany.
2
Institute of Functional Genomics, Regensburg University, 93053, Regensburg, Germany.
3
Institute of Biophysics, Ulm University, 89081, Ulm, Germany.
4
Genomics-Core Facility, Center for Biomedical Research, Ulm University Hospital, 89081, Ulm, Germany.
5
Department of Pharmacology and Clinical Neuroscience, Umeå University, 90187, Umeå, Sweden.
6
Department of Neurology, Hannover Medical School, 30625, Hannover, Germany.
7
Laboratory for Neuropathology, Institute of Pathology, Ulm University, 89081, Ulm, Germany.
8
Laboratory for Neuropathology, Department of Neurosciences, KU Leuven, 3000, Louvain, Belgium.
9
Department of Pathology, UZ Leuven, 3000, Louvain, Belgium.
10
Molecular Cardiology, Department of Internal Medicine II, Ulm University, 89081, Ulm, Germany.
11
Department of Neurology, Ulm University, Albert-Einstein-Allee 11, 89081, Ulm, Germany. jochen.weishaupt@uni-ulm.de.

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.

KEYWORDS:

Amyotrophic lateral sclerosis; Frontotemporal dementia; MicroRNA; Microtubules; TBCE; Zebrafish

PMID:
30030593
DOI:
10.1007/s00018-018-2873-1
[Indexed for MEDLINE]

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