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Endolysosomal pathway activity protects cells from neurotoxic TDP-43.
Leibiger, Christine; Deisel, Jana; Aufschnaiter, Andreas; Ambros, Stefanie; Tereshchenko, Maria; Verheijen, Bert M; Büttner, Sabrina; Braun, Ralf J.
Afiliação
  • Leibiger C; Institute of Cell Biology, University of Bayreuth, Universitätsstraße 30, 95447 Bayreuth, Germany.
  • Deisel J; Institute of Cell Biology, University of Bayreuth, Universitätsstraße 30, 95447 Bayreuth, Germany.
  • Aufschnaiter A; Institute of Molecular Biosciences, University of Graz, Humboldtstraße 50, 8010 Graz, Austria.
  • Ambros S; Institute of Cell Biology, University of Bayreuth, Universitätsstraße 30, 95447 Bayreuth, Germany.
  • Tereshchenko M; Institute of Cell Biology, University of Bayreuth, Universitätsstraße 30, 95447 Bayreuth, Germany.
  • Verheijen BM; Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.
  • Büttner S; Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Heidelberglaan 100, 3508 GA Utrecht, The Netherlands.
  • Braun RJ; Institute of Molecular Biosciences, University of Graz, Humboldtstraße 50, 8010 Graz, Austria.
Microb Cell ; 5(4): 212-214, 2018 Mar 21.
Article em En | MEDLINE | ID: mdl-29611555
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.
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Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2018 Tipo de documento: Article