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Cellular and Molecular Life Sciences

, Volume 75, Issue 23, pp 4301–4319 | Cite as

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

  • Anika M. Helferich
  • Sarah J. Brockmann
  • Jörg Reinders
  • Dhruva Deshpande
  • Karlheinz Holzmann
  • David Brenner
  • Peter M. Andersen
  • Susanne Petri
  • Dietmar R. Thal
  • Jens Michaelis
  • Markus Otto
  • Steffen Just
  • Albert C. Ludolph
  • Karin M. Danzer
  • Axel Freischmidt
  • Jochen H. WeishauptEmail author
Original Article

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 TBCE Microtubules Zebrafish 

Abbreviations

ALS

Amyotrophic lateral sclerosis

C9orf72

Chromosome 9 open reading frame 72

CASP3

Caspase-3

CNS

Central nervous system

DIV

Days in vitro

fALS

Familial ALS

miRNA

MicroRNA

miR-1825

MicroRNA-1825

POFUT1

Protein O-fucosyltransferase

pre-miRNA

Precursor microRNA

pri-miRNA

Primary microRNA

sALS

Sporadic ALS

TBCB

Tubulin-folding cofactor b

TBCE

Tubulin-folding cofactor e

TDP-43

Transactive response DNA-binding protein 43

TUBA4A

Tubulin alpha-4A

Notes

Acknowledgements

We are indebted to the patients and families participating in this study. We are also grateful to Elena Jasovski, Ramona Bück, Nadine Todt and Aline Sage for their excellent technical assistance. We also thank Lüder-Hinrich Meyer (Ulm University) for providing the dual-luciferase miRNA reporter plasmid and Jasmin Breymayer and Angelika Rück of the core facility confocal and multi-photon microscopy in Ulm for their help and technical advice. This work was supported in whole or in parts by grants from the German Federal Ministry of Education and Research (STRENGTH consortium/BMBF, 01GI0704; German network for ALS research (MND-NET)), the Charcot Foundation for ALS Research (ACL, JHW), and the DFG-funded Swabian ALS Registry.

Author contributions

AMH, SJB, JR, DD, AF and KH performed experiments and analyzed data. AMH, AF and JHW designed and supervised the study and interpreted the results. PMA, SP and DRT provided post-mortem tissue samples. JM, MO, ACL, DB, SJ and KMD helped conducting the study and provided critical input for scientific interpretations. AMH, AF and JHW wrote the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

18_2018_2873_MOESM1_ESM.pdf (1.4 mb)
Supplementary material 1 (PDF 1442 kb)
18_2018_2873_MOESM2_ESM.xlsx (321 kb)
Supplementary material 2 (XLSX 320 kb)

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Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Anika M. Helferich
    • 1
  • Sarah J. Brockmann
    • 1
  • Jörg Reinders
    • 2
  • Dhruva Deshpande
    • 3
  • Karlheinz Holzmann
    • 4
  • David Brenner
    • 1
  • Peter M. Andersen
    • 1
    • 5
  • Susanne Petri
    • 6
  • Dietmar R. Thal
    • 7
    • 8
    • 9
  • Jens Michaelis
    • 3
  • Markus Otto
    • 1
  • Steffen Just
    • 10
  • Albert C. Ludolph
    • 1
  • Karin M. Danzer
    • 1
  • Axel Freischmidt
    • 1
  • Jochen H. Weishaupt
    • 1
    Email author
  1. 1.Department of NeurologyUlm UniversityUlmGermany
  2. 2.Institute of Functional GenomicsRegensburg UniversityRegensburgGermany
  3. 3.Institute of BiophysicsUlm UniversityUlmGermany
  4. 4.Genomics-Core Facility, Center for Biomedical ResearchUlm University HospitalUlmGermany
  5. 5.Department of Pharmacology and Clinical NeuroscienceUmeå UniversityUmeåSweden
  6. 6.Department of NeurologyHannover Medical SchoolHannoverGermany
  7. 7.Laboratory for Neuropathology, Institute of PathologyUlm UniversityUlmGermany
  8. 8.Laboratory for Neuropathology, Department of NeurosciencesKU LeuvenLouvainBelgium
  9. 9.Department of PathologyUZ LeuvenLouvainBelgium
  10. 10.Molecular Cardiology, Department of Internal Medicine IIUlm UniversityUlmGermany

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