DNA Methyltransferase 1 (DNMT1) Acts on Neurodegeneration by Modulating Proteostasis-Relevant Intracellular Processes
International Journal of Molecular Sciences, vol. 21, pp. 5420
Abstract
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.
Authors 7
-
Cathrin Bayer Aachen Institute for Biology II Division of Functional Epigenetics in the Animal Model
Affiliation as printed
Division of Functional Epigenetics in the Animal Model, Institute for Biology II, RWTH Aachen University, Worringerweg 3, 52074 Aachen, Germany
-
Georg Pitschelatow Aachen Institute for Biology II Division of Functional Epigenetics in the Animal Model
Affiliation as printed
Division of Functional Epigenetics in the Animal Model, Institute for Biology II, RWTH Aachen University, Worringerweg 3, 52074 Aachen, Germany
-
Nina Hannemann Aachen Institute for Biology II Division of Functional Epigenetics in the Animal Model
Affiliation as printed
Division of Functional Epigenetics in the Animal Model, Institute for Biology II, RWTH Aachen University, Worringerweg 3, 52074 Aachen, Germany
-
Affiliation as printed
Division of Functional Epigenetics in the Animal Model, Institute for Biology II, RWTH Aachen University, Worringerweg 3, 52074 Aachen, Germany
-
Julia Reichard Aachen Institute for Biology II Division of Functional Epigenetics in the Animal Model
Affiliation as printed
Division of Functional Epigenetics in the Animal Model, Institute for Biology II, RWTH Aachen University, Worringerweg 3, 52074 Aachen, Germany
-
Daniel Pensold Aachen Institute for Biology II Division of Functional Epigenetics in the Animal Model
Affiliation as printed
Division of Functional Epigenetics in the Animal Model, Institute for Biology II, RWTH Aachen University, Worringerweg 3, 52074 Aachen, Germany
-
Geraldine Zimmer‐Bensch corresponding Aachen Institute for Biology II Division of Functional Epigenetics in the Animal Model
Affiliation as printed
Division of Functional Epigenetics in the Animal Model, Institute for Biology II, RWTH Aachen University, Worringerweg 3, 52074 Aachen, Germany
Cited by 21 stored of 21
No patents citing this paper on Lens.org (checked 2026-10-06).