Bonnifet Tom, Sinnassamy Sandra, Massiani-Beaudoin Olivia, Mailly Philippe, Monnet Heloise, Loew Damarys, Lombard Berangere, Servant Nicolas, Joshi Rajiv L, Fuchs Julia
CIRB, Collège de France, Université PSL, INSERM, Paris, France.
Orion Technological Core, CIRB, Collège de France, Université PSL, INSERM, CNRS, Paris, France.
Elife. 2025 Sep 25;13:RP100687. doi: 10.7554/eLife.100687.
Recent studies have established a reciprocal causal link between aging and the activation of transposable elements, characterized in particular by a de-repression of LINE-1 retrotransposons. These LINE-1 elements represent 21% of the human genome, but only a minority of these sequences retain the coding potential essential for their mobility. LINE-1 encoded proteins can induce cell toxicity implicated in aging and neurodegenerative diseases. However, our knowledge of the expression and localization of LINE-1-encoded proteins in the central nervous system is limited. Using a novel approach combining atlas-based brain mapping with deep-learning algorithms on large-scale pyramidal brain images, we unveil a heterogeneous, neuron-predominant, and widespread ORF1p expression throughout the murine brain at steady-state. In aged mice, ORF1p expression increases significantly, which is corroborated in human post-mortem dopaminergic neurons by an increase in young LINE-1 elements including those with open reading frames. Mass spectrometry analysis of endogenous mouse ORF1p revealed novel, neuron-specific protein interactors. These findings contribute to a comprehensive description of the dynamics of LINE-1 and ORF1p expression in the brain at steady-state and in aging and provide insights on ORF1p protein interactions in the brain.
