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Open AccessArticle

DNA Methyltransferase 1 (DNMT1) Acts on Neurodegeneration by Modulating Proteostasis-Relevant Intracellular Processes

Division of Functional Epigenetics in the Animal Model, Institute for Biology II, RWTH Aachen University, Worringerweg 3, 52074 Aachen, Germany
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(15), 5420; https://doi.org/10.3390/ijms21155420
Received: 11 July 2020 / Revised: 27 July 2020 / Accepted: 28 July 2020 / Published: 30 July 2020
(This article belongs to the Special Issue Cell Signaling in Neurodegeneration)
The limited regenerative capacity of neurons requires a tightly orchestrated cell death and survival regulation in the context of longevity, as well as age-associated and neurodegenerative diseases. Subordinate to genetic networks, epigenetic mechanisms, such as DNA methylation and histone modifications, are involved in the regulation of neuronal functionality and emerge as key contributors to the pathophysiology of neurodegenerative diseases. DNA methylation, a dynamic and reversible process, is executed by DNA methyltransferases (DNMTs). DNMT1 was previously shown to act on neuronal survival in the aged brain, whereby a DNMT1-dependent modulation of processes relevant for protein degradation was proposed as an underlying mechanism. Properly operating proteostasis networks are a mandatory prerequisite for the functionality and long-term survival of neurons. Malfunctioning proteostasis is found, inter alia, in neurodegenerative contexts. Here, we investigated whether DNMT1 affects critical aspects of the proteostasis network by a combination of expression studies, live cell imaging, and protein biochemical analyses. We found that DNMT1 negatively impacts retrograde trafficking and autophagy, with both being involved in the clearance of aggregation-prone proteins by the aggresome–autophagy pathway. In line with this, we found that the transport of GFP-labeled mutant huntingtin (HTT) to perinuclear regions, proposed to be cytoprotective, also depends on DNMT1. Depletion of Dnmt1 accelerated perinuclear HTT aggregation and improved the survival of cells transfected with mutant HTT. This suggests that mutant HTT-induced cytotoxicity is at least in part mediated by DNMT1-dependent modulation of degradative pathways. View Full-Text
Keywords: DNMT1; autophagy; degradation; aggresome; HTT; retrograde trafficking; Huntington’s disease DNMT1; autophagy; degradation; aggresome; HTT; retrograde trafficking; Huntington’s disease
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MDPI and ACS Style

Bayer, C.; Pitschelatow, G.; Hannemann, N.; Linde, J.; Reichard, J.; Pensold, D.; Zimmer-Bensch, G. DNA Methyltransferase 1 (DNMT1) Acts on Neurodegeneration by Modulating Proteostasis-Relevant Intracellular Processes. Int. J. Mol. Sci. 2020, 21, 5420.

AMA Style

Bayer C, Pitschelatow G, Hannemann N, Linde J, Reichard J, Pensold D, Zimmer-Bensch G. DNA Methyltransferase 1 (DNMT1) Acts on Neurodegeneration by Modulating Proteostasis-Relevant Intracellular Processes. International Journal of Molecular Sciences. 2020; 21(15):5420.

Chicago/Turabian Style

Bayer, Cathrin; Pitschelatow, Georg; Hannemann, Nina; Linde, Jenice; Reichard, Julia; Pensold, Daniel; Zimmer-Bensch, Geraldine. 2020. "DNA Methyltransferase 1 (DNMT1) Acts on Neurodegeneration by Modulating Proteostasis-Relevant Intracellular Processes" Int. J. Mol. Sci. 21, no. 15: 5420.

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