TY - JOUR T1 - <em>C9ORF72</em>-derived poly-GA DPRs undergo endocytic uptake in iAstrocytes and spread to motor neurons JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.202101276 VL - 5 IS - 9 SP - e202101276 AU - Paolo M Marchi AU - Lara Marrone AU - Laurent Brasseur AU - Audrey Coens AU - Christopher P Webster AU - Luc Bousset AU - Marco Destro AU - Emma F Smith AU - Christa G Walther AU - Victor Alfred AU - Raffaele Marroccella AU - Emily J Graves AU - Darren Robinson AU - Allan C Shaw AU - Lai Mei Wan AU - Andrew J Grierson AU - Stephen J Ebbens AU - Kurt J De Vos AU - Guillaume M Hautbergue AU - Laura Ferraiuolo AU - Ronald Melki AU - Mimoun Azzouz Y1 - 2022/09/01 UR - https://www.life-science-alliance.org/content/5/9/e202101276.abstract N2 - Dipeptide repeat (DPR) proteins are aggregation-prone polypeptides encoded by the pathogenic GGGGCC repeat expansion in the C9ORF72 gene, the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. 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 β-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 propagation, suggesting lysosomal impairment as a possible feature underlying the cellular pathogenicity of these DPR species. ER -