Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Histone acetylation/deacetylation is a master regulation of gene expression. Among the enzymes involved in this process, the CREB-binding protein (CBP) displays important functions during central nervous system development. Increasing evidence shows that CBP function is altered during neurodegenerative processes. CBP loss of function has now been reported in several diseases characterized by neurological disorders such as the Rubinstein-Taybi syndrome or polyglutamine-related pathologies (Huntington's disease). Our recent work suggests that CBP loss of function could also be involved in Alzheimer's disease and amyotrophic lateral sclerosis. In a simplified apoptotic model of primary neurons, we described CBP as a substrate of apoptotic caspases, an alternative to its classical proteasomal degradation. In these neuronal death contexts, histone acetylation levels were decreased as well. Altogether, these data point to a central role of CBP loss of function during neurodegeneration. In order to restore proper acetylation levels, a proposed therapeutic strategy relies on HDAC inhibition. Nevertheless, this approach lacks of specificity. Therefore new drugs targeted at counteracting CBP loss of function could stand as a valid therapeutic approach in neurodegenerative disorders. The challenge will be to respect the fine-tuning between cellular HAT/HDAC activities.
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PMID:Targeting CREB-binding protein (CBP) loss of function as a therapeutic strategy in neurological disorders. 1531 13

During the development and maintenance of the central nervous system, neurons receive specific instructions to differentiate, survive or die, the correct choice being crucial for the maturation of a functional brain and to face pathological conditions. At the transcriptional level, chromatin remodeling enzymes participates in such processes. In this paper, we will see that disruption of the Histone acetyl transferase (HAT)/Deacetylase (HDAC) balance is often observed in different contexts of neurological disorders and more particularly during neuronal apoptosis. During the last 5 years, it has been evidenced that the chromatin acetylation status was greatly impaired in different neurodegenerative diseases, a common mechanism being the loss of function of a specific HAT: the CREB-binding protein (CBP). We will review the last attempts of the use of small molecules antagonizing HDAC activity (HDAC inhibitors) to restore proper levels of acetylation and enhance neuronal survival, both in in vitro and in vivo models of neurodegenerative diseases such as polyglutamine-related diseases and amyotrophic lateral sclerosis. Although this strategy lacks specificity towards CBP, certain of these molecules display promising therapeutic properties
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PMID:Chromatin acetylation status in the manifestation of neurodegenerative diseases: HDAC inhibitors as therapeutic tools. 1748 32

Dysfunction of the heterogeneous ribonucleoprotein TAR DNA binding protein 43 (TDP-43) is associated with neurodegeneration in diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Here we examine the effects of a series of 4-aminoquinolines with affinity for TDP-43 upon caspase-7-induced cleavage of TDP-43 and TDP-43 cellular function. These compounds were mixed inhibitors of biotinylated TG6 binding to TDP-43, binding to both free and occupied TDP-43. Incubation of TDP-43 and caspase-7 in the presence of these compounds stimulated caspase-7 mediated cleavage of TDP-43. This effect was antagonized by the oligonucleotide TG12, prevented by denaturing TDP-43, and exhibited a similar relation of structure to function as for the displacement of bt-TG6 binding to TDP-43. In addition, the compounds did not affect caspase-7 enzyme activity. In human neuroglioma H4 cells, these compounds lowered levels of TDP-43 and increased TDP-43 C-terminal fragments via a caspase-dependent mechanism. Subsequent experiments demonstrated that this was due to induction of caspases 3 and 7 leading to increased PARP cleavage in H4 cells with similar rank order of the potency among the compounds tests for displacement of bt-TG6 binding. Exposure to these compounds also reduced HDAC-6, ATG-7, and increased LC3B, consistent with the effects of TDP-43 siRNA described by other investigators. These data suggest that such compounds may be useful biochemical probes to further understand both the normal and pathological functions of TDP-43, and its cleavage and metabolism promoted by caspases.
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PMID:Characterization of a series of 4-aminoquinolines that stimulate caspase-7 mediated cleavage of TDP-43 and inhibit its function. 2265 71

Dysregulation in acetylation homeostasis has been implicated in the pathogenesis of the amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. It is known that the acetylation of transcriptional factors regulates their activity. The acetylation state of NF-kB RelA has been found to dictate the neuroprotective versus the neurotoxic effect of p50/RelA. Here we showed that the pro-apoptotic acetylation mode of RelA, involving a general lysine deacetylation of the subunit with the exclusion of the lysine 310, is evident in the lumbar spinal cord of SOD1(G93A) mice, a murine model of ALS. The administration of the HDAC inhibitor MS-275 and the AMPK/sirtuin 1 activator resveratrol restored the normal RelA acetylation in SOD1(G93A) mice. The SOD1(G93A) mice displayed a 3 weeks delay of the disease onset, associated with improvement of motor performance, and 2 weeks increase of lifespan. The epigenetic treatment rescued the lumbar motor neurons affected in SOD1(G93A) mice, accompanied by increased levels of protein products of NF-kB-target genes, Bcl-xL and brain-derived neurotrophic factor. In conclusion, we here demonstrate that MS-275 and resveratrol restore the acetylation state of RelA in the spinal cord, delaying the onset and increasing the lifespan of SOD1(G93A) mice.
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PMID:Acetylation state of RelA modulated by epigenetic drugs prolongs survival and induces a neuroprotective effect on ALS murine model. 3015 Jul 70

TDP-43 pathology is a disease hallmark that characterizes both amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP). TDP-43 undergoes several posttranslational modifications that can change its biological activities and its aggregative propensity, which is a common hallmark of different neurodegenerative conditions. New evidence is provided by the current study pointing at TDP-43 acetylation in ALS cellular models. Using both in vitro and in vivo approaches, we demonstrate that TDP-43 interacts with histone deacetylase 1 (HDAC1) via RRM1 and RRM2 domains, that are known to contain the two major TDP-43 acetylation sites, K142 and K192. Moreover, we show that TDP-43 is a direct transcriptional activator of CHOP promoter and this activity is regulated by acetylation. Finally and most importantly, we observe both in cell culture and in Drosophila that a HDCA1 reduced level (genomic inactivation or siRNA) or treatment with pan-HDAC inhibitors exert a protective role against WT or pathological mutant TDP-43 toxicity, suggesting TDP-43 acetylation as a new potential therapeutic target. HDAC inhibition efficacy in neurodegeneration has long been debated, but future investigations are warranted in this area. Selection of more specific HDAC inhibitors is still a promising option for neuronal protection especially as HDAC1 appears as a downstream target of both TDP- 43 and FUS, another ALS-related gene.
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PMID:HDAC1 inhibition ameliorates TDP-43-induced cell death in vitro and in vivo. 3240 64

Environmental lead (Pb) exposure is closely associated with pathogenesis of a range of neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), attention deficit/hyperactivity disorder (ADHD), etc. Epigenetic machinery modulates neural development and activities, while faulty epigenetic regulation contributes to the diverse forms of CNS (central nervous system) abnormalities and diseases. As a potent epigenetic modifier, lead is thought to cause neurological disorders through modulating epigenetic mechanisms. Specifically, increasing evidence linked aberrant DNA methylations, histone modifications as well as ncRNAs (non-coding RNAs) with AD cases, among which circRNA (circular RNA) stands out as a new and promising field for association studies. In 23-year-old primates with developmental lead treatment, Zawia group discovered a variety of epigenetic changes relating to AD pathogenesis. This is a direct evidence implicating epigenetic basis in lead-induced AD animals with an entire lifespan. Additionally, some epigenetic molecules associated with AD etiology were also known to respond to chronic lead exposure in comparable disease models, indicating potentially interlaced mechanisms with respect to the studied neurotoxic and pathological events. Of note, epigenetic molecules acted via globally or selectively influencing the expression of disease-related genes. Compared to AD, the association of lead exposure with other neurological disorders were primarily supported by epidemiological survey, with fewer reports connecting epigenetic regulators with lead-induced pathogenesis. Some pharmaceuticals, such as HDAC (histone deacetylase) inhibitors and DNA methylation inhibitors, were developed to deal with CNS disease by targeting epigenetic components. Still, understandings are insufficient regarding the cause-consequence relations of epigenetic factors and neurological illness. Therefore, clear evidence should be provided in future investigations to address detailed roles of novel epigenetic factors in lead-induced neurological disorders, and efforts of developing specific epigenetic therapeutics should be appraised.
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PMID:Epigenetic Basis of Lead-Induced Neurological Disorders. 3264 24