Nuclear translocation of the LINE-1 encoded ORF1 protein alters nuclear envelope integrity in human neurons.

LINE-1 retrotransposons are increasingly implicated in aging and neurodegenerative diseases, yet the precise pathogenic mechanisms remain elusive. While the endonuclease and reverse transcriptase activities of LINE-1-encoded ORF2p can induce DNA damage and inflammation, a role of LINE-1 ORF1p in cellular dysfunctions stays unassigned. Here we demonstrate, using a neuronal cellular model, that ORF1p translocates into the nucleus upon arsenite-induced stress, directly interacting with nuclear import (KPNB1), nuclear pore complex (NUP153), and nuclear lamina (Lamin B1) proteins. Nuclear translocation of ORF1p disrupts nuclear integrity, nucleocytoplasmic transport, and heterochromatin structure, features linked to neurodegeneration and aging. Elevated nuclear ORF1p levels induced either by arsenite-induced stress, ORF1p overexpression, or as observed in Parkinson's disease post-mortem brain tissues correlate with impaired nuclear envelope (NE) morphology. Stress-induced nuclear alterations are mitigated by blocking ORF1p nuclear import or with the anti-aging drug remodelin. This study thus reveals a pathogenic action of nuclear ORF1p in human neurons driving NE alterations and thereby contributing to LINE-1-mediated cell toxicity.