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

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.

DNA Methyltransferase 1 (DNMT1) Shapes Neuronal Activity of Human iPSC-Derived Glutamatergic Cortical Neurons

“…Compared to cells treated only with control siRNA, the level of DNMT1 transcripts in cells, transfected with DNMT1 siRNA, was significantly reduced, confirming a successful knockdown ( Figure 2 a). We previously showed that such a siRNA-mediated depletion not only results in reduced transcript levels, but similarly diminishes DNMT1 protein levels within 24 h [ 31 , 32 ].…”

DNA methyltransferase expression (DNMT1, DNMT3a and DNMT3b) as a potential biomarker for anti-VEGF diabetic macular edema response

“…It will be important in the future to evaluate the evolution of the disease prospectively, therapeutic influence and vascular (vascular density through OCTA) and neurodegenerative (RNFL) changes. 39 In the future, a longitudinal approach will be important to clarify if the identified expression differences (1) reflect disease evolution, (2) translate the therapeutic impact, (3) or can help to predict the therapeutic resistance profile. In any case, in the perspective of precision medicine, epigenetic characterization and its relation with non-invasive structural biomarkers like SD-OCT could help clarify the best medicine practice in order to personalize the therapeutic response 12 and avoid permanent retinal lesions and irreversible blindness.…”

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

“…In Huntington disease, DNMT1 knockdown strengthens autophagy, and ameliorates Huntington-induced 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.…”