ImmunoSensation - the immune sensory system

Life Sci Alliance . 2021 Dec 21

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

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

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 β-sheet proteins (β 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, β proteins interact with and sequester AP-3 μ1, 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-3μ1 expression ameliorates neurotoxicity caused by β proteins. Altogether, our results highlight the link between protein aggregation, lysosomal impairments, and neurotoxicity.

PMID: 34933920