Endolysosomal pathway activity protects cells from neurotoxic TDP-43

Authors:

Christine Leibiger1,#, Jana Deisel1,#, Andreas Aufschnaiter2, Stefanie Ambros1, Maria Tereshchenko1, Bert M. Verheijen3,4, Sabrina Büttner2,5, and Ralf J. Braun1

doi: 10.15698/mic2018.04.627
Volume 5, pp. 212 to 214, published 21/03/2018.

PDF Download PubMed Link
Affiliations:

1 Institute of Cell Biology, University of Bayreuth, Universitätsstraße 30, 95447 Bayreuth, Germany.

2 Institute of Molecular Biosciences, University of Graz, Humboldtstraße 50, 8010 Graz, Austria.

3 Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.

4 Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Heidelberglaan 100, 3508 GA Utrecht, The Netherlands.

5 Department of Molecular Biosciences, The Wenner Gren Institute, Stockholm University, S-106 91 Stockholm, Sweden.

# Equally contributing authors.

Keywords: 

motor neuron disease, amyotrophic lateral sclerosis, frontotemporal dementia, TDP-43, protein aggregation, proteolysis, endolysosomal pathway, endosomal-vacuolar pathway, endocytosis, vacuole, lysosomes, autophagy, cell death, Saccharomyces cerevisiae

Corresponding Author(s):

Dr. Ralf Braun, , Institute of Cell Biology, University of Bayreuth, Universitätsstraße 30, 95447 Bayreuth; Germany; Phone: +49-921-55-4311; Fax: +49-921-55-4301; ralf.braun@uni-bayreuth.de

Conflict of interest statement:

The authors declare no conflict of interest.

Please cite this article as:

Christine Leibiger, Jana Deisel, Andreas Aufschnaiter, Stefanie Ambros, Maria Tereshchenko, Bert M. Verheijen, Sabrina Büttner, and Ralf J. Braun (2018). Endolysosomal pathway activity protects cells from neurotoxic TDP-43. Microbial Cell 5(4): 212-214. doi: 10.15698/mic2018.04.627

© 2018 Leibiger et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduction in any medium, provided the original author and source are acknowledged.

Abstract:

The accumulation of protein aggregates in neurons is a typical pathological hallmark of the motor neuron disease amyotrophic lateral sclerosis (ALS) and of frontotemporal dementia (FTD). In many cases, these aggregates are composed of the 43 kDa TAR DNA-binding protein (TDP‑43). Using a yeast model for TDP‑43 proteinopathies, we observed that the vacuole (the yeast equivalent of lysosomes) markedly contributed to the degradation of TDP‑43. This clearance occurred via TDP‑43-containing vesicles fusing with the vacuole through the concerted action of the endosomal-vacuolar (or endolysosomal) pathway and autophagy. In line with its dominant role in the clearance of TDP‑43, endosomal-vacuolar pathway activity protected cells from the detrimental effects of TDP‑43. In contrast, enhanced autophagy contributed to TDP‑43 cytotoxicity, despite being involved in TDP‑43 degradation. TDP‑43’s interference with endosomal-vacuolar pathway activity may have two deleterious consequences. First, it interferes with its own degradation via this pathway, resulting in TDP‑43 accumulation. Second, it affects vacuolar proteolytic activity, which requires endosomal-vacuolar trafficking. We speculate that the latter contributes to aberrant autophagy. In sum, we propose that ameliorating endolysosomal pathway activity enhances cell survival in TDP‑43-associated diseases.