C9orf72-derived poly-GA DPRs undergo endocytic uptake in iNPC-derived astrocytes and spread to motor neurons
Marchi, P. M.; Marrone, L.; Brasseur, L.; Bousset, L.; Webster, C. P.; Destro, M.; Walther, C. G.; Alfred, V.; Marroccella, R.; Robinson, D.; Shaw, A. C.; Wan, L. M.; Grierson, A.; Ebbens, S. J.; Hautbergue, G. M.; Ferraiuolo, L.; Melki, R.; Azzouz, M.
Show abstract
Dipeptide repeat proteins (DPRs) are aggregation-prone polypeptides encoded by the pathogenic G4C2 repeat expansion in the C9orf72 gene, the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). In this study, we focus on the role of poly-GA DPRs in disease spread. We demonstrate that recombinant poly-GA oligomers can directly convert into solid-like aggregates and form characteristic &[beta]-sheet fibrils in vitro. To dissect the process of cell-to-cell DPR transmission, we closely follow the fate of poly-GA DPRs in either their oligomeric or fibrillized form after administration in the cell culture medium. We observe that poly-GA DPRs are taken up via dynamin-dependent and - independent endocytosis, eventually converging at the lysosomal compartment and leading to axonal swellings in neurons. We then use a co-culture system to demonstrate astrocyte-to- motor neuron DPR propagation, showing that astrocytes may internalise and release aberrant peptides in disease pathogenesis. Overall, our results shed light on the mechanisms of poly- GA cellular uptake and cell-to-cell propagation, suggesting lysosomal impairment as a possible feature underlying the cellular pathogenicity of these DPR species.
Matching journals
The top 8 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- The LRRK2 G2019S mutation alters astrocyte-to-neuron communication via extracellular vesicles and induces neuron atrophy in a human iPSC-derived model of Parkinson's disease 96%
- APOE Expression and Secretion are Modulated by Mitochondrial Dysfunction 95%
- SNARE protein tomosyn regulates dense core vesicle composition but not exocytosis in mammalian neurons 95%
Similar papers in this journal
- Hexokinase 2 displacement from mitochondria-associated membranes prompts Ca2+-dependent death of cancer cells 94%
- ALIX and ceramide differentially control polarized exosome release from epithelial cells 94%
- 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 94%
Similar papers in this journal
- Glutamine deprivation regulates the origin and function of cancer cell exosomes 95%
- Local externalization of phosphatidylserine mediates developmental synaptic pruning by microglia 95%
- A balance between actin and Eps8/IRSp53 utilization in branched versus linear actin networks determines tunneling nanotube formation 94%
Similar papers in this journal
- A genome-wide CRISPR functional survey of the human phagocytosis molecular machinery 95%
- ERLIN1/2 scaffolds bridge TMUB1 and RNF170 and restrict cholesterol esterification to regulate the secretory pathway 95%
- Mechanistic Insights into the Protective Roles of Polyphosphate Against Amyloid Cytotoxicity 94%
Similar papers in this journal
- Phosphoinositide- and Collybistin-Dependent Synaptic Clustering of Gephyrin 94%
- Organelle phenotyping and multi-dimensional microscopy identify C1q as a novel regulator of microglial function. 94%
- Antibody-induced crosslinking and cholesterol-sensitive, anomalous diffusion of nicotinic acetylcholine receptors 93%
"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.