DNA methyltransferase 1 (DNMT1) function is implicated in the age-related loss of cortical interneurons

Abstract

36Increased life expectancy in modern society comes at the cost of age-associated disabilities and 37 diseases. Aged brains not only show reduced excitability and plasticity, but also a decline in 38 inhibition. Age-associated defects in inhibitory circuits likely contribute to cognitive decline and age-39 related disorders. Molecular mechanisms that exert epigenetic control of gene expression, contribute 40 Running Title 2 This is a provisional file, not the final typeset article to age-associated neuronal impairments. Both DNA methylation, mediated by DNA 41 methyltransferases (DNMTs), and histone modifications maintain neuronal function throughout 42 lifespan. Here we provide evidence that DNMT1 function is implicated in the age-related loss of 43 cortical inhibitory interneurons. Deletion of Dnmt1 in parvalbumin-positive interneurons attenuates 44 their age-related decline in the cerebral cortex. Moreover, DNMT1-deficient mice show improved 45 somatomotor performance and reduced aging-associated transcriptional changes. A decline in the 46 proteostasis network, responsible for the proper degradation and removal of defective proteins, is 47 suggested to be essentially implicated in age-and disease-related neurodegeneration. Our data 48 suggest that DNMT1 acts indirectly on interneuron survival in aged mice by modulating the 49 proteostasis network during life-time. 50 51

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

“…Due to their larger soma size, the dynamics and the temporal course of perinuclear HTT aggregation can be clearly identified by live cell imaging, in contrast to aggregation in the smaller-sized and roundish N2a cells. In line with our findings that Dnmt1 siRNA application increased the velocity of retrograde transport [ 11 ], we found that the formation of HTT-GFP aggregates was significantly faster upon siRNA-mediated depletion of Dnmt1 in CB cells ( Figure 4 ). This indicates that DNMT1 is involved in mutant HTT-induced cytotoxicity via modulation of aggresome formation by acting on retrograde transportation.…”

“…In previous studies, we identified that DNMT1 transcriptionally controls a variety of endosomal, lysosomal, and retrograde trafficking-associated genes in their expression, with most of them being repressed by DNMT1 in cortical interneurons [ 11 , 12 ] ( Figure 1 a and Supplementary Figure S1a ). Functionally, we confirmed that DNMT1 slows down the velocity of retrograde transportation of endolysosomal compartments in cerebellar granule (CB) cells [ 11 ], which we frequently use as a neuronal cell culture model [ 11 , 12 ]. Here, we verified whether retrograde transport is likewise modulated by DNMT1 in neuroblastoma (N2a) cells, in order to assess whether the regulation of retrograde transport is a more general, cellular sub-type independent function of DNMT1.…”

“…In contrast to its survival-promoting function in developing neural cells, we found that DNMT1 negatively influences cortical interneuron longevity in the aged brain [ 11 ]. However, no cell death or survival-related genes have been revealed to be targeted by DNMT1 function as an underlying cause.…”

“…However, no cell death or survival-related genes have been revealed to be targeted by DNMT1 function as an underlying cause. In turn, a significant enrichment of genes associated with proteostasis pathways were found to be suppressed by DNMT1, through which the effect on interneuron longevity could be mediated [ 10 , 11 , 12 ].…”

“…We have evidence that DNMT1 represses the expression of genes related to autophagy, perinuclear region, and intracellular microtubule trafficking events, such as endo-lysosomal transport, being crucial for degradative proteostasis networks [ 12 ]. Indeed, we found accelerated retrograde endosomal transport and trafficking of endocytosed cargo fated for lysosomal degradation upon Dnmt1 depletion [ 11 ]. As retrograde trafficking is central to the aggresome–autophagy pathway, and as neurons expressing polyglutamine-expanded Htt show improved survival when they form aggresomes [ 36 ], we here aimed to investigate whether DNMT1 is implicated in mutant HTT-induced cytotoxicity by acting on retrograde transport, aggresome formation, and autophagy.…”