RT Journal Article SR Electronic T1 Impact of α-Synuclein Fibrillar Strains and β-Amyloid Assemblies on Mouse Cortical Neurons Endo-Lysosomal Logistics JF eneuro JO eNeuro FD Society for Neuroscience SP ENEURO.0227-21.2022 DO 10.1523/ENEURO.0227-21.2022 VO 9 IS 3 A1 Qiao-Ling Chou A1 Ania Alik A1 François Marquier A1 Ronald Melki A1 François Treussart A1 Michel Simonneau YR 2022 UL http://www.eneuro.org/content/9/3/ENEURO.0227-21.2022.abstract AB Endosomal transport and positioning cooperate in the establishment of neuronal compartment architecture, dynamics, and function, contributing to neuronal intracellular logistics. Furthermore, dysfunction of endo-lysosomal has been identified as a common mechanism in neurodegenerative diseases. Here, we analyzed endo-lysosomal transport when α-synuclein (α-syn) fibrillar polymorphs, β-amyloid (Aβ) fibrils, and oligomers were externally applied on primary cultures of mouse cortical neurons. To measure this transport, we used a simple readout based on the spontaneous endocytosis in cultured neurons of fluorescent nanodiamonds (FNDs), a perfectly stable nano-emitter, and the subsequent automatic extraction and quantification of their directed motions at high-throughput. α-Syn fibrillar polymorphs, Aβ fibrils, and oligomers induce a 2-fold decrease of the fraction of nanodiamonds transported along microtubules, while only slightly reducing their interaction with cortical neurons. This important decrease in moving endosomes is expected to have a huge impact on neuronal homeostasis. We next assessed lysosomes dynamics, using LysoTracker. Neurons exposure to Aβ oligomers led to an increase in the number of lysosomes, a decrease in the fraction of moving lysosome and an increase in their size, reminiscent of that found in APP transgenic model of Alzheimer’s disease. We then analyzed the effect of α-syn fibrillar polymorphs, Aβ fibrils, and oligomers on endosomal and lysosomal transport and quantified directed transport of those assemblies within cortical neurons. We report different impacts on endosomal and lysosomal transport parameters and differences in the trajectory lengths of cargoes loaded with pathogenic protein assemblies. Our results suggest that intraneuronal pathogenic protein aggregates internalization and transport may represent a target for novel neuroprotective therapeutic strategies.