RT Journal Article
SR Electronic
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
FD Life Science Alliance LLC
SP e202101276
DO 10.26508/lsa.202101276
VO 5
IS 9
A1 Paolo M Marchi
A1 Lara Marrone
A1 Laurent Brasseur
A1 Audrey Coens
A1 Christopher P Webster
A1 Luc Bousset
A1 Marco Destro
A1 Emma F Smith
A1 Christa G Walther
A1 Victor Alfred
A1 Raffaele Marroccella
A1 Emily J Graves
A1 Darren Robinson
A1 Allan C Shaw
A1 Lai Mei Wan
A1 Andrew J Grierson
A1 Stephen J Ebbens
A1 Kurt J De Vos
A1 Guillaume M Hautbergue
A1 Laura Ferraiuolo
A1 Ronald Melki
A1 Mimoun Azzouz
YR 2022
UL https://www.life-science-alliance.org/content/5/9/e202101276.abstract
AB 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.