Huntington's disease (HD) is caused by a dominant polyglutamine expansion within the N-terminus of huntingtin protein and results in oxidative stress, energetic insufficiency and striatal degeneration. Copper and iron are increased in the striata of HD patients, but the role of these metals in HD pathogenesis is unknown. We found, using inductively-coupled-plasma mass spectroscopy, that elevations of copper and iron found in human HD brain are reiterated in the brains of affected HD transgenic mice. Increased brain copper correlated with decreased levels of the copper export protein, amyloid precursor protein. We hypothesized that increased amounts of copper bound to low affinity sites could contribute to pro-oxidant activities and neurodegeneration. We focused on two proteins: huntingtin, because of its centrality to HD, and lactate dehydrogenase (LDH), because of its documented sensitivity to copper, necessity for normoxic brain energy metabolism and evidence for altered lactate metabolism in HD brain. The first 171 amino acids of wild-type huntingtin, and its glutamine expanded mutant form, interacted with copper, but not iron. N171 reduced Cu2+ in vitro in a 1∶1 copper∶protein stoichiometry indicating that this fragment is very redox active. Further, copper promoted and metal chelation inhibited aggregation of cell-free huntingtin. We found decreased LDH activity, but not protein, and increased lactate levels in HD transgenic mouse brain. The LDH inhibitor oxamate resulted in neurodegeneration when delivered intra-striatially to healthy mice, indicating that LDH inhibition is relevant to neurodegeneration in HD. Our findings support a role of pro-oxidant copper-protein interactions in HD progression and offer a novel target for pharmacotherapeutics.
Cystamine, a small disulfide-containing chemical, is neuroprotective in a transgenic mouse and a Drosophila model of Huntington's disease (HD) and decreases huntingtin aggregates in an in vitro model of HD. The mechanism of action of cystamine in these models is widely thought to involve inhibition of transglutaminase mediated cross-linking of mutant huntingtin in the process of aggregate formation/stabilization. In this study we show that cystamine, both in vitro and in a transgenic mouse model of HD (R6/2), increases levels of the cellular antioxidant L-cysteine. Several oxidative stress markers increase in HD brain. We provide further evidence of oxidative stress in mouse HD by demonstrating compensatory responses in R6/2 HD brains. We found age-dependent increases in forebrain glutathione (GSH), and increased levels of transcripts coding for proteins involved in GSH synthesis and detoxification pathways, as revealed by quantitative PCR analysis. Given the general importance of oxidative stress as a mediator of neurodegeneration we propose that an increase in brain L-cysteine levels could be protective in HD. Furthermore, cystamine was dramatically protective against 3-nitropropionic acid-induced striatal injury in mice. We suggest that cystamine's neuroprotective effect in HD transgenic mice results from pleiotropic effects that include transglutaminase inhibition and antioxidant activity.
Huntington disease (HD) is a progressive neurodegenerative disease that affects 30,000 individuals in North America. Treatments that slow its relentless course are not yet available, and biomarkers that can reliably measure disease activity and therapeutic response are urgently needed to facilitate their development. Here, we interrogated 119 human blood samples for transcripts associated with HD. We found that the dynamic regulator of chromatin plasticity H2A histone family, member Y (H2AFY) is specifically overexpressed in the blood and frontal cortex of patients with HD compared with controls. This association precedes the onset of clinical symptoms, was confirmed in two mouse models, and was independently replicated in cross-sectional and longitudinal clinical studies comprising 142 participants. A histone deacetylase inhibitor that suppresses neurodegeneration in animal models reduces H2AFY levels in a randomized phase II clinical trial. This study identifies the chromatin regulator H2AFY as a potential biomarker associated with disease activity and pharmacodynamic response that may become useful for enabling disease-modifying therapeutics for HD.
Interactions between mutant huntingtin (Htt) and a variety of transcription factors including specificity proteins (Sp) have been suggested as a central mechanism in Huntington disease (HD). However, the transcriptional activity induced by Htt in neurons that triggers neuronal death has yet to be fully elucidated. In the current study, we characterized the relationship of Sp1 to Htt protein aggregation and neuronal cell death. We found increased levels of Sp1 in neuronal-like PC12 cells expressing mutant Htt, primary striatal neurons, and brain tissue of HD transgenic mice. Sp1 levels were also elevated when 3-nitropropionate (3-NP) was used to induce cell death in PC12 cells. To assess the effects of knocking down Sp1 in HD pathology, we used Sp1 siRNA, a heterozygous Sp1 knock-out mouse, and mithramycin A, a DNA-intercalating agent that inhibits Sp1 function. The three approaches consistently yielded reduced levels of Sp1 which ameliorated toxicity caused by either mutant Htt or 3-NP. In addition, when HD mice were crossed with Sp1 heterozygous knock-out mice, the resulting offspring did not experience the loss of dopamine D2 receptor mRNA characteristic of HD mice, and survived longer than their HD counterparts. Our data suggest that enhancement of transcription factor Sp1 contributes to the pathology of HD and demonstrates that its suppression is beneficial. Huntington disease (HD)2 is a fatal hereditary neurodegenerative disorder characterized by progressive motor and cognitive deficits caused by neuronal dysfunction and degeneration affecting selected populations of neurons. The genetic defect responsible for HD is a CAG repeat expansion in exon 1 of the HD gene leading to the expression of a mutant huntingtin (Htt) protein containing an abnormally long polyglutamine sequence (1). Direct interactions between mutant Htt and a variety of transcription factors have been identified, which may significantly contribute to the pathogenesis of HD (2, 3). Gene microarray studies have indicated that selective transcriptional alterations occur early in HD (4), consistent with transcriptional dysregulation (5-7). Many of the altered genes contain binding sites for Sp1, which we recently demonstrated to interact with Htt in a polyglutamine lengthdependent manner (2).Sp1 is a zinc-finger domain (C terminus) transcriptional activator (8) that has been implicated in the expression of many genes in concert with other transcription factors, including the TAFII family (2), CREB (3, 9), nuclear factor-B (10), and vesicular endothelial growth factor receptor-2 (VEGFR-2) (11, 12). Sp1-mediated processes include aberrant transcriptional modulation of dopamine receptor genes, neurodegeneration (2, 13, 14), and inflammatory processes (12, 15), which are important in the pathogenesis of HD. However, various in vitro studies have implicated Sp1 as being prosurvival (16,17) or prodeath (18, 19), or involved in neurodegeneration (10,14). Whereas interactions between Sp1 and mutant huntingtin appear to be deleterious at the molecular l...
Periodontitis is a chronic inflammatory disease of supporting structures of teeth. Macular degeneration which is a common cause of blindness in older population is found to be associated with periodontitis. This systematic review summaries the findings concerning the relation between periodontitis and macular degeneration.
CitationR Chopra, H Saxena. Detection of species -and tissue -unrestricted conformation -dependent tumor associated antigen(s) in immune complexes from plasma of tumor affected cattle and buffaloes. AbstractRabbit hyperimmune serum against intact whole immune complexes from a mammary tumor affected dog gave positive reactivity in dot ELISA with plasma from cattle and buffaloes affected with various tumors compared to sera against the antigen -rich and the antibody -rich fractions of dissociated circulating immune complexes (CICs). These results suggest a possibility of existence of species -and tissue -unrestricted tumor associated antigens (TAAs) as conformation -dependent epitope(s) in CICs in bovine tumors.
Genetics and epigenetics is the process of gene expression or suppression through polymorphism, demethylation, and deacetylation. Although Periodontal diseases are bacterial infections predominantly gram negative anaerobic bacteria that colonize the sub gingivaly in return triggering an inflammatory response which affect the periodontium; whereas periodontitis is a periodontal disease which destroys the tissue and bone that surrounds the tooth. In adults periodontitis is at helm of tooth loss. Pathogenic microrgansims are considered as the primary aetiological factor, but the disease progression is also influenced by Genotype and Phenotype of various individuals. Phenotypic factors such as race, diabetes, gender, education, smoking etc. have sweeping effects on the epigenetic changes and impel susceptibility to disease. Epigenetic modifications expression occur in response to environmental changes.
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