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TDP-43 controls lysosomal pathways thereby determining its own clearance and cytotoxicity
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Number of Authors: 82018 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 27, no 9, p. 1593-1607Article in journal (Refereed) Published
Abstract [en]

TDP-43 is a nuclear RNA-binding protein whose cytoplasmic accumulation is the pathological hallmark of amyotrophic lateral sclerosis (ALS). For a better understanding of this devastating disorder at the molecular level, it is important to identify cellular pathways involved in the clearance of detrimental TDP-43. Using a yeast model system, we systematically analyzed to which extent TDP-43-triggered cytotoxicity is modulated by conserved lysosomal clearance pathways. We observed that the lysosomal fusion machinery and the endolysosomal pathway, which are crucial for proper lysosomal function, were pivotal for survival of cells exposed to TDP-43. Interestingly, TDP-43 itself interfered with these critical TDP-43 clearance pathways. In contrast, autophagy played a complex role in this process. It contributed to the degradation of TDP-43 in the absence of endolysosomal pathway activity, but its induction also enhanced cell death. Thus, TDP-43 interfered with lysosomal function and its own degradation via lysosomal pathways, and triggered lethal autophagy. We propose that these effects critically contribute to cellular dysfunction in TDP-43 proteinopathies.

Place, publisher, year, edition, pages
2018. Vol. 27, no 9, p. 1593-1607
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Biochemistry and Molecular Biology Cell Biology
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URN: urn:nbn:se:su:diva-156606DOI: 10.1093/hmg/ddy066ISI: 000431882900008PubMedID: 29474575OAI: oai:DiVA.org:su-156606DiVA, id: diva2:1210999
Available from: 2018-05-30 Created: 2018-05-30 Last updated: 2018-05-30Bibliographically approved

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Büttner, Sabrina
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Department of Molecular Biosciences, The Wenner-Gren Institute
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