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  Amyloid-like aggregating proteins cause lysosomal defects in neurons via gain-of-function toxicity

Riera Tur, I., Schäfer, T., Hornburg, D., Mishra, A., da Silva Padilha, M., Fernández-Mosquera, L., et al. (2022). Amyloid-like aggregating proteins cause lysosomal defects in neurons via gain-of-function toxicity. Life science alliance, 5(3): e202101185. doi:10.26508/lsa.202101185.

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Riera Tur, Irene1, 2, Author              
Schäfer, Tillmann, Author
Hornburg, Daniel, Author
Mishra, Archana2, Author              
da Silva Padilha, Miguel1, 2, Author              
Fernández-Mosquera, Lorena, Author
Feigenbutz, Dennis1, 2, Author              
Auer, Patrick1, 2, Author              
Mann, Matthias, Author
Baumeister, Wolfgang, Author
Klein, Rüdiger2, Author              
Meissner, Felix, Author
Raimundo, Nuno, Author
Fernandez-Busnadiego, Ruben, Author
Dudanova, Irina1, 2, Author              
Affiliations:
1Research Group: Molecular Neurodegeneration / Dudanova, MPI of Neurobiology, Max Planck Society, ou_3060199              
2Department: Molecules-Signaling-Development / Klein, MPI of Neurobiology, Max Planck Society, ou_1113546              

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 Abstract: The autophagy-lysosomal pathway is impaired in many neurodegenerative diseases characterized by protein aggregation, but the link between aggregation and lysosomal dysfunction remains poorly understood. Here, we use artificial amyloid-like β-sheet proteins (β proteins) to investigate the gain-of-function effects of protein aggregation in primary neurons. We show that β proteins form fibrillar aggregates and cause neurotoxicity. Cryo-electron tomography reveals lysosomal alterations reminiscent of lysosomal storage disorders. Mass spectrometry-based analysis of the β protein interactome shows that β proteins sequester AP-3μ1, a subunit of the AP-3 adaptor complex involved in protein trafficking to lysosomal organelles. Importantly, restoring AP-3μ1 expression ameliorates neurotoxicity caused by β proteins. Our results point to lysosomes as particularly vulnerable organelles in neurodegenerative diseases, and emphasize the role of toxic gain-of-function of protein aggregates in lysosomal defects.

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 Dates: 2022-03-01
 Publication Status: Published in print
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 Rev. Type: Peer
 Identifiers: DOI: 10.26508/lsa.202101185
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Title: Life science alliance
  Abbreviation : Life Sci Alliance
Source Genre: Journal
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Publ. Info: Heidelberg : EMBO Press
Pages: - Volume / Issue: 5 (3) Sequence Number: e202101185 Start / End Page: - Identifier: ISSN: 2575-1077
CoNE: https://pure.mpg.de/cone/journals/resource/2575-1077