20.500.12556/RUL-184880 LINE-1 Retrotransposons and Amyotrophic Lateral Sclerosis 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. amiotrophic lateral sclerosis LINE-1 retrotranspons TDP-43 cGAS-STING neuroinflammation epigenetic dysregulation amiotrofična laterna skleroza LINE-1 retrotransposons TDP-43 cGAS-STING nevrovnetje epigenetska disregulacija true false true Angleški jezik Slovenski jezik Članek v reviji 2026-07-16 12:03:49 2026-07-16 12:03:50 2026-07-18 03:32:18 0000-00-00 00:00:00 2026 0 0 Str. 1-23 iss. 14, art. 6244 Vol. 27 2026 0000-00-00 Zaloznikova Objavljeno apc 0000-00-00 0000-00-00 0000-00-00 577.2 1661-6596 10.3390/ijms27146244 284996611 RAZ_Korosec_Tinkara_2026.pdf RAZ_Korosec_Tinkara_2026.pdf 1 8283DB917508DC4B794FD86C667871D7 92530f650a5782555a2800d3359a27d325fd3a6681cec9420cf293155a1a1c5b cae25509-80fd-11f1-9b0d-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=240268 https://www.mdpi.com/1422-0067/27/14/6244 1 7557cffd-80fd-11f1-9b0d-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=240266 Fakulteta za kemijo in kemijsko tehnologijo Biotehniška fakulteta 0 0 0