α-Synuclein Sequesters Dnmt1 from the Nucleus

Abstract

DNA methylation is a major epigenetic modification that regulates gene expression. Dnmt1, the maintenance DNA methylation enzyme, is abundantly expressed in the adult brain and is mainly located in the nuclear compartment, where it has access to chromatin. Hypomethylation of CpG islands at intron 1 of the SNCA gene has recently been reported to result in overexpression of ␣-synuclein in Parkinson disease (PD) and related disorders. We therefore investigated the mechanisms underlying altered DNA methylation in PD and dementia with Lewy bodies (DLB). We present evidence of reduction of nuclear Dnmt1 levels in human postmortem brain samples from PD and DLB patients as well as in the brains of ␣-synuclein transgenic mice models. Furthermore, sequestration of Dnmt1 in the cytoplasm results in global DNA hypomethylation in human and mouse brains, involving CpG islands upstream of SNCA, SEPW1, and PRKAR2A genes. We report that association of Dnmt1 and ␣-synuclein might mediate aberrant subcellular localization of Dnmt1. Nuclear Dnmt1 levels were partially rescued by overexpression of Dnmt1 in neuronal cell cultures and in ␣-synuclein transgenic mice brains. Our results underscore a novel mechanism for epigenetic dysregulation in Lewy body diseases, which might underlie the decrease in DNA methylation reported for PD and DLB. Parkinson disease (PD)2 and dementia with Lewy bodies (DLB) belong to a heterogeneous group of neurodegenerative disorders known as Lewy body diseases, which are characterized by ␣-synuclein (␣-syn) accumulation in Lewy body structures (1, 2). The most striking pathological feature of PD is the loss of dopaminergic neurons in the substantia nigra, although neurodegeneration has been also reported to occur in the cortex. In DLB, non-motor cognitive alterations appear before parkinsonism and ␣-syn accumulates mainly in the limbic system and neocortical areas, suggesting that these structures have an important role in disease (3). At the molecular level, accumulation of misfolded ␣-syn affects mitochondrial function, autophagy (4), and the expression of several functional groups of genes (5, 6), although the molecular basis of transcriptional dysregulation remain elusive.Proper gene expression is crucial for the cell, and therefore, it is tightly regulated by the binding of regulatory proteins to promoter regions and by the epigenetic remodeling of the chromatin structure by DNA methylation and histone modifications. Although the traditional concept of epigenetics refers to stable and heritable changes associated with cell division and development, there is mounting evidence supporting that DNA methylation is dynamically regulated in postmitotic neurons, having crucial roles in memory formation and synaptic plasticity (7). Altered epigenetic mechanisms have also been associated with neurological disorders, including Rett syndrome, autism, schizophrenia, and Alzheimer, Huntington, and Parkinson diseases (8). The relevance of DNA methylation in PD pathology was highlighted recently by two studies showin...

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