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

Riera Tur, Irene; Schäfer, Tillmann; Hornburg, Daniel; Mishra, Archana; da Silva Padilha, Miguel; Fernández-Mosquera, Lorena; Feigenbutz, Dennis; Auer, Patrick; Mann, Matthias; Baumeister, Wolfgang; Klein, Rüdiger; Meissner, Felix; Raimundo, Nuno; Fernandez-Busnadiego, Ruben; Dudanova, Irina

doi:10.26508/lsa.202101185

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

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Riera Tur, Irene
Research Group: Molecular Neurodegeneration / Dudanova, MPI of Neurobiology, Max Planck Society;
Department: Molecules-Signaling-Development / Klein, MPI of Neurobiology, Max Planck Society;

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Mishra, Archana
Department: Molecules-Signaling-Development / Klein, MPI of Neurobiology, Max Planck Society;

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da Silva Padilha, Miguel
Research Group: Molecular Neurodegeneration / Dudanova, MPI of Neurobiology, Max Planck Society;
Department: Molecules-Signaling-Development / Klein, MPI of Neurobiology, Max Planck Society;

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Feigenbutz, Dennis
Research Group: Molecular Neurodegeneration / Dudanova, MPI of Neurobiology, Max Planck Society;
Department: Molecules-Signaling-Development / Klein, MPI of Neurobiology, Max Planck Society;

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Auer, Patrick
Research Group: Molecular Neurodegeneration / Dudanova, MPI of Neurobiology, Max Planck Society;
Department: Molecules-Signaling-Development / Klein, MPI of Neurobiology, Max Planck Society;

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Klein, Rüdiger
Department: Molecules-Signaling-Development / Klein, MPI of Neurobiology, Max Planck Society;

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Dudanova, Irina
Research Group: Molecular Neurodegeneration / Dudanova, MPI of Neurobiology, Max Planck Society;
Department: Molecules-Signaling-Development / Klein, MPI of Neurobiology, Max Planck Society;

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Citation

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.

Cite as: https://hdl.handle.net/21.11116/0000-0006-DC5D-B

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.