Amyloid-like aggregates cause lysosomal defects in neurons via gain-of-function toxicity
Schaefer, T.; Riera-Tur, I.; Hornburg, D.; Mishra, A.; Fernandez-Mosquera, L.; Raimundo, N.; Mann, M.; Baumeister, W.; Klein, R.; Meissner, F.; Fernandez-Busnadiego, R.; Dudanova, I.
Show 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 combine cryo-electron tomography, proteomics and cell biology studies to investigate the effects of protein aggregates in primary neurons. We use artificial amyloid-like {beta}-sheet proteins ({beta} proteins) to focus on the gain-of-function aspect of aggregation. These proteins form fibrillar aggregates and cause neurotoxicity. We show that late stages of autophagy are impaired by the aggregates, resulting in lysosomal alterations reminiscent of lysosomal storage disorders. Mechanistically, {beta} proteins interact with and sequester AP-31, a subunit of the AP-3 adaptor complex involved in protein trafficking to lysosomal organelles. This leads to destabilization of the AP-3 complex, missorting of AP-3 cargo, and lysosomal defects. Restoring AP-31 expression ameliorates neurotoxicity caused by {beta} proteins. Altogether, our results highlight the link between protein aggregation and neurotoxicity, pointing to lysosomes as particularly vulnerable organelles.
Matching journals
The top 5 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- SNARE protein tomosyn regulates dense core vesicle composition but not exocytosis in mammalian neurons 97%
- Aβ-driven nuclear pore complex dysfunction alters activation of necroptosis proteins in a mouse model of Alzheimer's Disease 96%
- APOE Expression and Secretion are Modulated by Mitochondrial Dysfunction 96%
Similar papers in this journal
Similar papers in this journal
- Loss of the lysosomal protein CLN3 modifies the lipid content of the nuclear envelope leading to DNA damage and activation of YAP1 pro-apoptotic signaling 95%
- LTK and ALK regulate neuronal polarity and cortical migration by modulating IGF1R activity 95%
- Enzymatic degradation of RNA causes widespread protein aggregation in cell and tissue lysates 95%
Similar papers in this journal
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.