Immune-mediated neurodegenerative trait provoked by multimodal derepression of long-interspersed nuclear element-1

• DOI: 10.1016/j.isci.2022.104278
• Publication Date: 2022-04-22T16:05:57Z
• Authors: Fumio Takahashi; Chenyang Zhang; Hirohiko Hohjoh; Ben Raveney; Takashi Yamamura; Nobuhiro Hayashi; Shinji Oki
• Keywords: Biological sciences; 0303 health sciences; 03 medical and health sciences; Science; Immunology; Q; Article; Neuroscience; 3. Good health

Neurodegeneration is a process involving both cell autonomous and non-cell autonomous neuron loss, followed by a collapse of neural networks, but its pathogenesis is poorly understood. We have previously demonstrated that Eomes-positive helper T (Eomes + Th) cells recognizing LINE-1(L1)-derived prototypic antigen ORF1 mediate neurotoxicity associated with the neurodegenerative pathology of experimental autoimmune encephalomyelitis (EAE). Here, we show that Eomes + Th cells accumulate in the CNS of mouse models of authentic neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD), and secrete the neurotoxic granzyme B after encounter with ORF1 antigen. Multimodal derepression of neuronal L1 transcription is observed in EAE and ALS/AD models during neurodegeneration in active and cell cycle-mediated manner, respectively. These data suggest that the adventitious concurrence of immune-mediated neurodegenerative traits by Eomes + Th cells and ectopic expression of L1-derived antigen(s) in the inflamed CNS may materialize a communal and previously unappreciated pathogenesis of neurodegeneration.