ArticleLife science alliance2022
Amyloid-like aggregating proteins cause lysosomal defects in neurons via gain-of-function toxicity.
Article in Life science alliance, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 26 citations in OpenAlex.
- Neurodegeneration risk variants promote lysosomal TMEM106B fibril accumulation.bioRxiv : the preprint server for biology · 2026Article
- Lysosomal swelling triggers LRRK2 activity.bioRxiv : the preprint server for biology · 2025Article
- Review
- CHIP protects lysosomes from CLN4 mutant-induced membrane damage.Nature cell biology · 2025Article
- Lysosomal targeting of liposomes with acidic pH and Cathepsin B induces protein aggregate clearance.Cell communication and signaling : CCS · 2025Article
- HSP110 is a modulator of amyloid beta (Aβ) aggregation and proteotoxicity.Journal of neurochemistry · 2025Article
- Therapeutic effects of a novel synthetic α-secretase.Frontiers in aging neuroscience · 2024Article
- Handling Difficult Cryo-ET Samples: A Study with Primary Neurons from Drosophila melanogaster.Microscopy and microanalysis : the official journal of Microscopy Society of America, Microbeam Analysis Society, Microscopical Society of Canada · 2023Article
- Mechanisms and pathology of protein misfolding and aggregation.Nature reviews. Molecular cell biology · 2023Review
- Article
- Lysosomal positioning diseases: beyond substrate storage.Open biology · 2022Review
- Gel-like inclusions of C-terminal fragments of TDP-43 sequester stalled proteasomes in neurons.EMBO reports · 2022Article
- A cryo-ET survey of microtubules and intracellular compartments in mammalian axons.The Journal of cell biology · 2022Article
Corrections and comments
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Authors and funding
15 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
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 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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.