The DNA methyltransferase 1 (DNMT1) acts on neurodegeneration by modulating proteostasis-relevant intracellular processes

Bayer, Cathrin; Pitschelatow, Georg; Hannemann, Nina; Linde, Jenice; Reichard, Julia; Pensold, Daniel; Zimmer-Bensch, Geraldine

doi:10.1101/2020.07.10.197442

Cited by 8 publications

(2 citation statements)

References 82 publications

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“…In Huntington disease, DNMT1 knockdown strengthens autophagy, and ameliorates Huntingtoninduced cytotoxicity. 45 Decrease of autophagy activity is occurring upon aging and thought to contribute to aging-related diseases. It uncovers, upon autophagy induction, de novo DNMT3A-mediated DNA methylation on expression of LC3 results in reduced baseline autophagy activity.…”

Section: Autophagy and Its Main Regulatory Mechanismmentioning

confidence: 99%

Epigenetic and post-translational modifications in autophagy: biological functions and therapeutic targets

Shu

Han

et al. 2023

Sig Transduct Target Ther

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Autophagy is a conserved lysosomal degradation pathway where cellular components are dynamically degraded and re-processed to maintain physical homeostasis. However, the physiological effect of autophagy appears to be multifaced. On the one hand, autophagy functions as a cytoprotective mechanism, protecting against multiple diseases, especially tumor, cardiovascular disorders, and neurodegenerative and infectious disease. Conversely, autophagy may also play a detrimental role via pro-survival effects on cancer cells or cell-killing effects on normal body cells. During disorder onset and progression, the expression levels of autophagy-related regulators and proteins encoded by autophagy-related genes (ATGs) are abnormally regulated, giving rise to imbalanced autophagy flux. However, the detailed mechanisms and molecular events of this process are quite complex. Epigenetic, including DNA methylation, histone modifications and miRNAs, and post-translational modifications, including ubiquitination, phosphorylation and acetylation, precisely manipulate gene expression and protein function, and are strongly correlated with the occurrence and development of multiple diseases. There is substantial evidence that autophagy-relevant regulators and machineries are subjected to epigenetic and post-translational modulation, resulting in alterations in autophagy levels, which subsequently induces disease or affects the therapeutic effectiveness to agents. In this review, we focus on the regulatory mechanisms mediated by epigenetic and post-translational modifications in disease-related autophagy to unveil potential therapeutic targets. In addition, the effect of autophagy on the therapeutic effectiveness of epigenetic drugs or drugs targeting post-translational modification have also been discussed, providing insights into the combination with autophagy activators or inhibitors in the treatment of clinical diseases.

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Section: Autophagy and Its Main Regulatory Mechanismmentioning

confidence: 99%

Epigenetic and post-translational modifications in autophagy: biological functions and therapeutic targets

Shu

Han

et al. 2023

Sig Transduct Target Ther

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“…In turn, various genes related to the proteostasis network were affected by the loss of DNMT1 function in young mice. Functional validation studies revealed that DNMT1 negatively influences subcellular processes implicated in endolysosomal protein degradation pathways [ 5 ], as well as in autophagy [ 97 ]. In line with that, defects in endocytosis, and endolysosomal protein degradation have already been described to be involved in age- and disease-related neurodegeneration [ 98 , 99 , 100 , 101 ].…”

Section: Implications Of Epigenetic Mechanisms In the Regulation Of Neuronal Survival And Functionality In The Healthy Brainmentioning

confidence: 99%

Epigenomic Remodeling in Huntington’s Disease—Master or Servant?

Zimmer-Bensch

2020

Epigenomes

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In light of our aging population, neurodegenerative disorders are becoming a tremendous challenge, that modern societies have to face. They represent incurable, progressive conditions with diverse and complex pathological features, followed by catastrophic occurrences of massive neuronal loss at the later stages of the diseases. Some of these disorders, like Huntington’s disease (HD), rely on defined genetic factors. HD, as an incurable, fatal hereditary neurodegenerative disorder characterized by its mid-life onset, is caused by the expansion of CAG trinucleotide repeats coding for glutamine (Q) in exon 1 of the huntingtin gene. Apart from the genetic defect, environmental factors are thought to influence the risk, onset and progression of HD. As epigenetic mechanisms are known to readily respond to environmental stimuli, they are proposed to play a key role in HD pathogenesis. Indeed, dynamic epigenomic remodeling is observed in HD patients and in brains of HD animal models. Epigenetic signatures, such as DNA methylation, histone variants and modifications, are known to influence gene expression and to orchestrate various aspects of neuronal physiology. Hence, deciphering their implication in HD pathogenesis might open up new paths for novel therapeutic concepts, which are discussed in this review.

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Roles of Aging, Circular RNAs, and RNA Editing in the Pathogenesis of Amyotrophic Lateral Sclerosis: Potential Biomarkers and Therapeutic Targets

Hosaka

Toda

Kwak

2023

Cells

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Amyotrophic lateral sclerosis (ALS) is an incurable motor neuron disease caused by upper and lower motor neuron death. Despite advances in our understanding of ALS pathogenesis, effective treatment for this fatal disease remains elusive. As aging is a major risk factor for ALS, age-related molecular changes may provide clues for the development of new therapeutic strategies. Dysregulation of age-dependent RNA metabolism plays a pivotal role in the pathogenesis of ALS. In addition, failure of RNA editing at the glutamine/arginine (Q/R) site of GluA2 mRNA causes excitotoxicity due to excessive Ca2+ influx through Ca2+-permeable α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors, which is recognized as an underlying mechanism of motor neuron death in ALS. Circular RNAs (circRNAs), a circular form of cognate RNA generated by back-splicing, are abundant in the brain and accumulate with age. Hence, they are assumed to play a role in neurodegeneration. Emerging evidence has demonstrated that age-related dysregulation of RNA editing and changes in circRNA expression are involved in ALS pathogenesis. Herein, we review the potential associations between age-dependent changes in circRNAs and RNA editing, and discuss the possibility of developing new therapies and biomarkers for ALS based on age-related changes in circRNAs and dysregulation of RNA editing.

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The DNA methyltransferase 1 (DNMT1) acts on neurodegeneration by modulating proteostasis-relevant intracellular processes

Cited by 8 publications

References 82 publications

Epigenetic and post-translational modifications in autophagy: biological functions and therapeutic targets

Epigenetic and post-translational modifications in autophagy: biological functions and therapeutic targets

Epigenomic Remodeling in Huntington’s Disease—Master or Servant?

Roles of Aging, Circular RNAs, and RNA Editing in the Pathogenesis of Amyotrophic Lateral Sclerosis: Potential Biomarkers and Therapeutic Targets

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