Epigenetic Changes in Neurodegenerative Diseases

Abstract

Afflicted neurons in various neurodegenerative diseases generally display diverse and complex pathological features before catastrophic occurrence of massive neuronal loss at the late stages of the diseases. This complex nature of neuronal pathophysiology inevitably implicates systemwide changes in basic cellular activities such as transcriptional controls and signal cascades, and so on, as a cause. Recently, as one of these systemwide cellular changes associated with neurodegenerative diseases, epigenetic changes caused by protein toxicity have begun to be highlighted. Notably, recent advances in related techniques including next-generation sequencing (NGS) and mass spectrometry enable us to monitor changes in the post-translational modifications (PTMs) of histone proteins and to link these changes in histone PTMs to the specific transcriptional changes. Indeed, epigenetic alterations and consequent changes in neuronal transcriptome are now begun to be extensively studied in neurodegenerative diseases including Alzheimer’s disease (AD). In this review, we will discuss details of our current understandings on epigenetic changes associated with two representative neurodegenerative diseases [AD and polyglutamine (polyQ) diseases] and further discuss possible future development of pharmaceutical treatment of the diseases through modulating these epigenetic changes.

Mechanisms of protein toxicity in neurodegenerative diseases

“…Similar to polyQ diseases, AD and PD also manifest epigenetic alterations, though the mechanisms of which remain to be elucidated [20, 31]. Nevertheless, treatment with certain epigenetic drugs, such as HDAC inhibitors, ameliorated AD and PD phenotypes in animal models [31], indicative of the relevance and importance of epigenetic alterations in the disease pathogenesis.…”

“…This view proposes that the more soluble protofibrillar or oligomeric aggregates (as opposed to the more mature fibrillar aggregates formed inside the nucleus) have toxic properties in afflicted neurons [ 14 – 18 ]. Whether or not the nuclear inclusion bodies are the major source of nuclear protein toxicity, nuclear dysfunctions such as transcriptional alteration and impaired nucleocytoplasmic transport are evident in many cases of neurodegenerative diseases [ 19 , 20 ].…”

Cellular Senescence in Neurodegenerative Diseases

“…Besides, in AD brains histone modifications have been linked to the reduction in transcription of genes that are implicated in neuronal physiology and increased the transcription of genes that are normally silenced (Berson et al, 2018). The phosphorylated histone H3 presents an altered localization of the cytoplasm, while the levels of the acetylated histone H4 are decreased in AD patients (Kwon et al, 2016).…”

An epigenetic role for ascorbic acid in neurodegenerative diseases

“…This reaction is catalyzed by DNA methyltransferases using S-adenosylmethionine as the source of the methyl group.There is increasing evidence that epigenetic mechanisms of gene expression are involved in the development of neurodegenerative diseases. 3,4 In recent years, ascorbic acid has been found to have a role in epigenetic mechanisms of gene expression. 5 In 2013, several groups showed that ascorbic acid serves as a cofactor for the ten-eleventen translocation (TET) dioxygenases.…”

“…5 Abnormalities in the concentrations and/or activities of 5mC and 5hmC in the brain have been implicated in the development of neurodegenerative diseases. 4,10 As ascorbic acid is associated with 5mC and 5hmC, abnormalities in the concentration and/or activity of ascorbic acid in the brain could be associated with the development of these diseases. I suggest that in addition to the ways by which ascorbic acid may be associated with neurodegenerative diseases suggested by Moretti et al, 1 ascorbic acid could also be associated epigenetically with the development of neurodegenerative diseases.…”