Program > Browse abstracts by author > Joshi Rajiv L

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.