Steady-state neuron-predominant LINE-1 encoded ORF1p protein and LINE-1 RNA increase with aging in the mouse and human brain
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Abstract
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.
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- Authors
- Bonnifet, T., Sinnassamy, S., Massiani-Beaudoin, O., Mailly, P., Monnet, H., Loew, D., Lombard, B., Servant, N., Joshi, R. L., & Fuchs, J.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Orion Technological Core, CIRB, Collège de France, Université PSL, INSERM, CNRS
- Université Paris Sciences et Lettres (FR)
- Institut Curie, Université PSL, Centre de Recherche, CurieCoreTech Spectrométrie de Masse Protéomique
- Inserm (FR)
- Corresponding author
- Joshi, Rajiv L
- Fuchs, Julia
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2025-09-25
- Volume
- 13
- Issue
- 13
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC12463392
- OpenAlex
- W4402308943
- Cited by
- 4
- References
- 11
- Citations by year
- 2026: 4
- Type
- posted content
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- HAL (submittedVersion, cc-by-nc)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Fondation de France (00086320)
- Fondation du Collège de France
- Institut de France (Fondation NRJ)
- FONDATION ALZHEIMER
- Fédération pour la Recherche sur le Cerveau
- Agence Nationale de la Recherche (ANR-20-CE16-0022 NEURAGE)
- Topics
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- LINE-1 retrotransposons, ORF1p, transposable elements, brain aging, neuron-specific expression, dopaminergic neurons, protein interactors, neurodegeneration, mouse brain, brain atlas
- MeSH terms
- Aging, Animals, Brain, Female, Humans, Male, Mice, Inbred C57BL, Neurons, Proteins, Long Interspersed Nucleotide Elements, Mice
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