C9ORF72-derived poly-GA DPRs undergo endocytic uptake in iAstrocytes and spread to motor neurons

Autor: Paolo M Marchi, Lara Marrone, Laurent Brasseur, Audrey Coens, Christopher P Webster, Luc Bousset, Marco Destro, Emma F Smith, Christa G Walther, Victor Alfred, Raffaele Marroccella, Emily J Graves, Darren Robinson, Allan C Shaw, Lai Mei Wan, Andrew J Grierson, Stephen J Ebbens, Kurt J De Vos, Guillaume M Hautbergue, Laura Ferraiuolo, Ronald Melki, Mimoun Azzouz
Přispěvatelé: University of Sheffield, Sheffield Institute for Translational Neuroscience, University of Sheffield [Sheffield], Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Centre for Membrane Interactions and Dynamics, ANR-17-JPCD-0002,TransPathND,Intraneuronal transport-related pathways across neurodegenerative diseases(2017), ANR-11-INBS-0010,METABOHUB,Développement d'une infrastructure française distribuée pour la métabolomique dédiée à l'innovation(2011), ANR-11-IDEX-0003,IPS,Idex Paris-Saclay(2011), European Project: 294745,EC:FP7:ERC,ERC-2011-ADG_20110310,GTNCTV(2012)
Rok vydání: 2022
Předmět:
Zdroj: Life Science Alliance
Life Science Alliance, 2022, 5 (9), pp.e202101276. ⟨10.26508/lsa.202101276⟩
ISSN: 2575-1077
DOI: 10.26508/lsa.202101276
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: