LINE-1 Retrotransposons and Amyotrophic Lateral Sclerosis

Korošec, Tinkara (author), Rogelj, Boris (author), Župunski, Vera (author)

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive degeneration of upper and lower motor neurons. While monogenic causes account for a minority of cases, in most cases, ALS is sporadic and likely arises from multilayer interactions of genetic architecture, aging-associated loss of genome regulation, and inflammatory stress. Long interspersed nuclear element-1 (LINE-1) retrotransposons are endogenous mobile elements that are tightly controlled through various cellular mechanisms under normal conditions. When abnormally active, they are involved in gene inactivation, expression regulation, and genomic instability, leading to cellular processes such as innate immunity and cell death. Here, we present mechanistic links between LINE-1 and ALS. These include evidence that the burden of retrotransposition-competent LINE-1s (RC-L1s) is increased in ALS genomes, positioning RC-L1 load as a candidate contributor to missing heritability in sporadic disease. We also integrate emerging data showing that LINE-1 RNA can be intrinsically toxic independently of new insertions, as it promotes chromatin opening and transcriptional epigenetic noise, particularly when nuclear RNA surveillance pathways fail in TDP-43 pathology. Finally, we review how LINE-1-derived DNA/RNA intermediates can engage innate immune sensors, highlighting the cGAS–STING axis as a plausible route from LINE-1 de-repression to neuroinflammation. Together, these concepts support a model in which genetic RC-L1 load and age-/pathology-driven LINE-1 de-repression converge on nuclear dysfunction and inflammatory amplification, suggesting concrete molecular nodes for therapeutic intervention.

• Language: English
• Keywords: amiotrophic lateral sclerosis, LINE-1, retrotranspons, TDP-43, cGAS-STING, neuroinflammation, epigenetic dysregulation
• Work type: Article
• Typology: 1.02 - Review Article
• Organization: FKKT - Faculty of Chemistry and Chemical Technology; BF - Biotechnical Faculty
• Publication status: Published
• Publication version: Version of Record
• Year: 2026
• Number of pages: Str. 1-23
• Numbering: Vol. 27, iss. 14, art. 6244
• PID: 20.500.12556/RUL-184880
• UDC: 577.2
• ISSN on article: 1661-6596
• DOI: 10.3390/ijms27146244
• COBISS.SI-ID: 284996611
• Publication date in RUL: 16.07.2026

Record is a part of a journal

• Title: International journal of molecular sciences
• Shortened title: Int. j. mol. sci.
• Publisher: MDPI
• ISSN: 1661-6596
• COBISS.SI-ID: 36217605

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: amiotrofična laterna skleroza, LINE-1, retrotransposons, TDP-43, cGAS-STING, nevrovnetje, epigenetska disregulacija