|
Neurodegenerative diseases are a heterogenous group of complex disorders linked by the degeneration of neurons in either the peripheral nervous system or the central nervous system. Their underlying causes are extremely variable and complicated by various genetic and/or environmental factors. These diseases cause progressive deterioration of the neuron resulting in decreased signal transduction and in some cases even neuronal death. Peripheral nervous system (PNS) diseases may be further categorized by the type of nerve cell (motor, sensory, or both) affected by the disorder. Effective treatment of these diseases is often prevented by lack of understanding of the underlying molecular and genetic pathology. Epigenetic therapy is being investigated as a method of correcting the expression levels of misregulated genes in neurodegenerative diseases. Neurodengenerative diseases of motor neurons can cause degeneration of motor neurons involved in voluntary muscle control such as muscle contraction and relaxation. This article will cover the epigenetics and treatment of Amyotrophic lateral sclerosis (ALS) and Spinal muscular atrophy (SMA). See the (Motor Neuron Fact Sheet ) for details regarding other motor neuron diseases. Neurodegenerative diseases of the central nervous system can affect the brain and/or spinal cord. This article will cover the epigenetics and treatment of Alzheimer’s disease (AD), Huntington’s disease (HD), and Parkinson’s disease (PD). These diseases are characterized by chronic and progressive neuronal dysfunction, sometimes leading to behavioral abnormalities (as with PD), and, ultimately, neuronal death, resulting in dementia. Neurodegeneration Neurodegenerative diseases of sensory neurons can cause degeneration of sensory neurons involved in transmitting sensory information such as hearing and seeing. The main group of sensory neuron diseases are hereditary sensory and autonomic neuropathies (HSAN) such as HSAN I, HSAN II, and Charcot-Marie-Tooth Type 2B (CMT2B).〔((OMIM ); Sghirlanzoni et al., 2005)〕 Though some sensory neuron diseases are recognized as neurodegenerative, epigenetic factors have not yet been clarified in the molecular pathology and as such will not be covered in this article. See the (Sensory neuron ) article for details. == Epigenetics and epigenetic drugs == The term epigenetics refers to three levels of gene regulation: (1) DNA methylation, (2) histone modifications, and (3) non-coding RNA (ncRNA) function. Briefly, histone-mediated transcriptional control occurs by the wrapping of DNA around a histone core. This DNA-histone structure is called a nucleosome; the more tightly the DNA is bound by the nucleosome, and the more tightly a string of nucleosomes are compressed among each other, the greater the repressive effect on transcription of genes in the DNA sequences near or wrapped around the histones, and vice versa (i.e. looser DNA binding and relaxed compaction leads to a comparatively derepressed state, resulting in facultative heterochromatin or, even further derepressed, euchromatin). At its most repressive state, involving many folds into itself and other scaffolding proteins, DNA-histone structures form constitutive heterochromatin. This chromatin structure is mediated by these three levels of gene regulation. The most relevant epigenetic modifications to treatment of neurodegenerative diseases are DNA methylation and histone protein modifications via methylation or acetylation.〔(Goll et al., 2005; Bradley et al., 2007)〕 :In mammals, methylation occurs on DNA and histone proteins. DNA methylation occurs on the cytosine of CpG dinucleotides in the genomic sequence, and protein methylation occurs on the amino termini of the core histone proteins - most commonly on lysine residues (Bradley et al., 2007). CpG refers to a dinucleotide composed of a cytosine deoxynucleotide immediately adjacent to a guanine deoxynucleotide. A cluster of CpG dinucleotides clustered together is called a CpG island, and in mammals, these CpG islands are one of the major classes of gene promoters, onto or around which transcription factors may bind and transcription can begin. Methylation of CpG dinucleotides and/or islands within gene promoters is associated with transcriptional repression via interference of transcription factor binding and recruitment of transcriptional repressors with methyl binding domains. Methylation of intragenic regions is associated with increased transcription. The group of enzymes responsible for addition of methyl groups to DNA are called DNA methyltransferases (DNMTs). The enzyme responsible for removal of methyl group are called DNA demethylases. The effects of histone methylation are residue dependent (e.g. which amino acid on which histone tail is methylated) therefore the resulting transcriptional activity and chromatin regulation can vary.〔(Bradley et al., 2007)〕 The enzymes responsible for the addition of methyl groups to histones are called histone methyltransferases (HMTs). The enzymes responsible for the removal of methyl groups from histone are histone demethylases. :Acetylation occurs on the lysine residues found at the amino N-terminal of histone tails. Histone acetylation is most commonly associated with relaxed chromatin, transcriptional derepression, and thus actively transcribed genes (Bradley et al., 2007). Histone acetyltransferases (HATs) are enzymes responsible for the addition of acetyl groups, and histone deacetylases (HDACs) are enzymes responsible for the removal of acetyl groups. Therefore, the addition or removal of an acetyl group to a histone can alter the expression of nearby genes. The majority of drugs being investigated are inhibitors of proteins that remove acetyl from histones or histone deacetylases (HDACs). :Briefly, ncRNAs are involved in signaling cascades with epigenetic marking enzymes such as HMTs, and/or with RNA interference(RNAi) machinery. Frequently these signaling cascades result in epigenetic repression (for one example, see X-chromosome inactivation), though there are some cases in which the opposite is true. For example, ''BACE1-AS'' ncRNA expression is upregulated in Alzheimer's disease patients and results in increased stability of ''BACE1'' - the mRNA precursor to an enzyme involved in Alzheimer's disease (Faghihi et al., 2008). See below for more detail. Epigenetic drugs target the proteins responsible for modifications on DNA or histone. Current epigenetic drugs include but are not limited to: HDAC inhibitors (HDACi), HAT modulators, DNA methyltransferase inhibitors, and histone demethylase inhibitors (Urdinguio et al., 2009; Peedicayil, 2013). The majority of epigenetic drugs tested for use against neurodegenerative diseases are HDAC inhibitors; however, some DNMT inhibitors have been tested as well. While the majority of epigenetic drug treatments have been conducted in mouse models, some experiments have been performed on human cells as well as in human drug trials (see table below). There are inherent risks in using epigenetic drugs as therapies for neurodegenerative disorders as some epigenetic drugs (e.g. HDACis such as sodium butyrate) are non-specific in their targets, which leaves potential for off-target epigenetic marks causing unwanted epigenetic modifications. : Disease: Amyotrophic Lateral Sclerosis (ALS), Alzheimer’s Disease (AD), Huntington's (HD), Spinal Muscular Atrophy (SMA), Parkinson's Disease (PD) : Tested on: mouse (M), only mouse cells (MC), human (H), Drosophila (D), rat (R) : Successful treatment: yes (y), yes but with side effects (ys), not yet (ny), variable (v), no improvement (ni) : References: ''listed by column (disease) and by ascending row (drug) order'' :: ALS: (1) Del Signore et al., 2009; Petri et al., 2006 (2) Cudkowicz et al., 2009 (3) Piepers et al., 2009; (4) Yoo et al., 2011 :: AD: (5) Fischer et al., 2007; (6) Ricobaraza et al., 2010; (7) Govindarajan et al., 2011; (8) Ricobaraza et al., 2012; (9) Kilgore et al., 2010; (10) Francis et al., 2009 :: HD: (11) Steffan et al., 2001 (12) Gardian et al., 2005 (13) Dompierre et al., 2007 :: PD: (14) Zhou et al., 2011 (15) Rane et al., 2012 (16) St. Laurent et al., 2013 (17) Monti et al., 2010 (18) Kontopolous et al., 2006 :: SMA: (19) Riessland et al., 2006 (20) Andreassi et al., 2004 (21) Mercuri et al., 2007 (22) Brahe et al., 2005 (23) Sumner et al., 2003 (24) Brichta et al., 2003 (25) Tsai et al., 2006 (26) Weihl et al., 2006 (27) Piepers et al., 2010 (28) Swoboda et al., 2010 (29) Darbar et al., 2011 (30) Narver et al., 2008 (31) Avila et al., 2007 (32) Hahnan et al., 2006 (33) Kernochan et al., 2005 (34) Riessland et al., 2010 抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』 ■ウィキペディアで「Epigenetics of neurodegenerative diseases」の詳細全文を読む スポンサード リンク
|