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

ABSTRACT: 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.

SUBMITTER: Takahashi F

PROVIDER: S-EPMC9097630 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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

Takahashi Fumio F Zhang Chenyang C Hohjoh Hirohiko H Raveney Ben B Yamamura Takashi T Hayashi Nobuhiro N Oki Shinji S

iScience 20220422 5

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 ...[more]

PMID: 35573205

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Project description:BackgroundRetrotransposition of long interspersed nuclear element-1 (L1-RTP) is proposed to contribute to central nervous system (CNS) plasticity by inducing mosaicism of neuronal cells. Clinical studies have identified increased L1 copy numbers in the brains of patients with psychiatric disorders. These observations implicate that L1-RTP is important for neurogenesis and that its deregulation represents a risk factor for mental disorders. However, no supportive evidence is available for understanding the importance of L1-RTP in CNS function.FindingsTo explore the physiological role of L1-RTP in CNS, we examined the L1 copy number during maturation. Interestingly, the L1 copy number increased after birth in the mouse hippocampus, but not the frontal lobe, with maximal copy numbers found in 8-week-old mice. This age-dependent L1 increase was abolished by administration of a reverse-transcriptase inhibitor, stavudine (d4T), which showed no toxic effects. Notably, the age-dependent L1 increase was attenuated by post-weaning social isolation (SI) stress, a well-known intervention for inducing psychiatric disorders in mice, or deletion of the NR2A gene that encodes a subunit of the glutamate receptor. Moreover, the negative effects of SI stress on L1-RTP were partially restored by environmental enrichment with voluntary running, but not by fluoxetine, a commonly used anti-psychiatric drug. Finally, behavioral experiments revealed that learning memory was defective in d4T-treated mice, which was similarly observed in mice raised under SI stress.ConclusionWe detected the modulation of L1-RTP in the hippocampus during maturation of the CNS. In a recent study, we demonstrated that stimulants such as methamphetamine and cocaine were active in the induction of L1-RTP in neuronal cells, and previous studies have shown that NR2A-deficient mice are susceptible to mental abnormality. Herein, our data support the notion that the age-dependent modulation of L1-RTP is involved in genome differentiation in the hippocampus, and that modulation defects are linked to the development of psychiatric disorders.

Project description:Although, increased oxidative stress and hypomethylation of long interspersed nuclear element-1 (LINE-1) associate with bladder cancer (BCa) development, the relationship between these alterations is unknown. We evaluated the oxidative stress and hypomethylation of the LINE-1 in 61 BCa patients and 45 normal individuals. To measure the methylation levels and to differentiate the LINE-1 loci into hypermethylated, partially methylated and hypomethylated, peripheral blood cells, urinary exfoliated cells and cancerous tissues were evaluated by combined bisulfite restriction analysis PCR. The urinary total antioxidant status (TAS) and plasma protein carbonyl content were determined. The LINE-1 methylation levels and patterns, especially hypomethylated loci, in the blood and urine cells of the BCa patients were different from the levels and patterns in the healthy controls. The urinary TAS was decreased, whereas the plasma protein carbonyl content was increased in the BCa patients relative to the controls. A positive correlation between the methylation of LINE-1 in the blood-derived DNA and urinary TAS was found in both the BCa and control groups. The urinary hypomethylated LINE-1 loci and the plasma protein carbonyl content provided the best diagnostic potential for BCa prediction. Based on post-diagnostic samples, the combination test improved the diagnostic power to a sensitivity of 96% and a specificity of 96%. In conclusion, decreased LINE-1 methylation is associated with increased oxidative stress both in healthy and BCa subjects across the various tissue types, implying a dose-response association. Increases in the LINE-1 hypomethylation levels and the number of hypomethylated loci in both the blood- and urine-derived cells and increase in the oxidative stress were found in the BCa patients. The combination test of the urinary hypomethylated LINE-1 loci and the plasma protein carbonyl content may be useful for BCa screening and monitoring of treatment.

Dataset Information

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

Publications

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

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