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Nuclear translocation of LINE-1 encoded ORF1p alters nuclear envelope integrity in human neurons
Julia Fuchs  1, 2@  , Rania Znaidi  3  , Tom Bonnifet  4  , Sandra Sinnassamy  2  , Olivia Massiani-Beaudoin  2  , Philippe Mailly  2  , Heloise Monnet  2  , Damarys Loew  5  , Bérangère Lombard  5  , Rajiv L Joshi  2  
1 : Centre for Interdisciplinary Research in Biology  (CIRB)
Collège de France, Institut National de la Santé et de la Recherche Médicale - INSERM : U1050, Centre National de la Recherche Scientifique - CNRS : UMR7241, PSL Research University
11, place Marcelin-Berthelot, 75231 Paris Cedex 05 -  France
2 : Centre interdisciplinaire de recherche en biologie
Collège de France, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, PSL Research University
11 place Marcellin Berthelot 75005 Paris -  France
3 : Centre for Interdisciplinary Research in Biology
Collège de France, Institut National de la Santé et de la Recherche Médicale - INSERM, Centre National de la Recherche Scientifique - CNRS, PSL Research University
11, place Marcelin-Berthelot, 75231 Paris Cedex 05 -  France
4 : Centre interdisciplinaire de recherche en biologie
Collège de France, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, PSL Research Uiversity
11 place Marcellin Berthelot 75005 Paris -  France
5 : Institut Curie, PSL University, Centre de Recherche, CurieCoreTech Spectrométrie de Masse Protéomique
Institut Curie, PSL Research University
26, rue d'Ulm, Paris 75248 Cedex 5 -  France

LINE-1 retrotransposons are emerging as possible culprits in neurodegenerative diseases and provide novel targets for disease-modifying therapies. However, the molecular mechanisms underlying the pathogenic role of LINE-1 and their encoded proteins ORF1p and ORF2p are still not completely understood. While the endonuclease and reverse transcriptase activity of ORF2p has been associated with DNA damage and inflammation, no pathogenic role has yet been assigned to ORF1p. To address this question, we established an in vitro human neuronal model displaying a robust increase of LINE-1 activity and ORF1p upon application of arsenite. ORF1p increase was accompanied by a loss of nuclear envelope integrity, disruption of nucleo-cytoplasmic transport including the cytoplasmic mislocalization of TDP-43 and heterochromatin destructuration, which are established or emerging features of aging and/or associated with neurodegenerative diseases. Arsenite-favored translocation of ORF1p into the nucleus was mediated by interaction of ORF1p with nuclear import receptors, nuclear pore complex components and nuclear lamina proteins. Blocking ORF1p nuclear import or stabilizing the nuclear envelope with the small molecule remodelin normalized nuclear ORF1p levels and restored nuclear envelope integrity, nucleo-cytoplasmic transport and heterochromatin organization. Overexpression of ORF1p in the absence of arsenite recapitulated nuclear envelope dysfunctions and loss of nuclear circularity correlated with nuclear ORF1p levels. This study thus reveals a retrotransposition-independent pathogenic action of ORF1p perturbing nuclear envelope integrity.

 



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