Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There are coding mutations in the prion protein gene in familial Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker disease, and other phenotypes that make up the inherited prion diseases. Insertional mutations consisting of two, five, six, seven, eight, and nine additional octapeptide repeat elements are seen in the inherited prion diseases and usually present as atypical dementias with considerable intrafamilial phenotypic variability. A four-octarepeat insertion was reported previously in an individual without neurodegenerative disease who died of hepatic cirrhosis. Here we report a novel four-octarepeat insertional mutation in a case with classical clinical, electroencephalographic and histopathologic features of CJD with the unusual finding of pronounced prion protein immunoreactivity of the molecular layer of the cerebellum.
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PMID:A prion disease with a novel 96-base pair insertional mutation in the prion protein gene. 861 79

Conformational diseases such as amyloidosis, Alzheimer's disease, prion diseases, and the serpinopathies are all caused by structural rearrangements within a protein that transform it into a pathological species. These diseases are typified by the Z variant of alpha(1)-antitrypsin (E342K), which causes the retention of protein within hepatocytes as inclusion bodies that are associated with neonatal hepatitis and cirrhosis. The inclusion bodies result from the Z mutation perturbing the conformation of the protein, which facilitates a sequential interaction between the reactive center loop of one molecule and beta-sheet A of a second. Therapies to prevent liver disease must block this reactive loop-beta-sheet polymerization without interfering with other proteins of similar tertiary structure. We have used reactive loop peptides to explore the differences between the pathogenic Z and normal M alpha(1)-antitrypsin. The results show that the reactive loop is likely to be partially inserted into beta-sheet A in Z alpha(1)-antitrypsin. This conformational difference from M alpha(1)-antitrypsin was exploited with a 6-mer reactive loop peptide (FLEAIG) that selectively and stably bound Z alpha(1)-antitrypsin. The importance of this finding is that the peptide prevented the polymerization of Z alpha(1)-antitrypsin and did not significantly anneal to other proteins (such as antithrombin, alpha(1)-antichymotrypsin, and plasminogen activator inhibitor-1) with a similar tertiary structure. These findings provide a lead compound for the development of small molecule inhibitors that can be used to treat patients with Z alpha(1)-antitrypsin deficiency. Furthermore they demonstrate how a conformational disease process can be selectively inhibited with a small peptide.
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PMID:6-mer peptide selectively anneals to a pathogenic serpin conformation and blocks polymerization. Implications for the prevention of Z alpha(1)-antitrypsin-related cirrhosis. 1177 44

The serpin superfamily of serine proteinase inhibitors has a central role in controlling proteinases in many biological pathways in a wide range of species. The inhibitory function of the serpins involves a marked conformational transition, but this inherent molecular flexibility also renders the serpins susceptible to point mutations that result in aberrant intermolecular linkage and polymer formation. The effects of such protein aggregation are cumulative, with a progressive loss of cellular function that results in diseases as diverse as cirrhosis and emphysema. The recent recognition that mutations in a serpin can also result in late-onset dementia provides insights into changes that underlie other conformational diseases, such as the amyloidoses, the prion encephalopathies and Huntington and Alzheimer diseases.
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PMID:Serpinopathies and the conformational dementias. 1236 Feb 34

A decreased effective arterial blood volume is the principal haemodynamic disturbance in cirrhosis, leading to activation of the renin angiotensin aldosterone and the sympathetic nervous systems, sodium and water retention and renal impairment. Albumin is a plasma expander that could be used in clinical settings in cirrhosis in which plasma expansion would reverse some of the decreased effective arterial blood volume, or prevent its iatrogenic (i.e., paracenteses) or spontaneous worsening (spontaneous bacterial peritonitis). However, apart from the issue of transmission of prion agents, which may become an important issue in clinical risk management of the use of albumin in the future, the problem with albumin is its expense. Every effort must thus be made to definitely prove albumin is always the best colloid for all clinical settings in cirrhosis. Further randomized trials are justified.
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PMID:Is the use of albumin of value in cirrhosis? The case not so in favour, or is there an alternative? 1456 92

Repeating intermolecular protein association by means of beta-sheet expansion is the mechanism underlying a multitude of diseases including Alzheimer's, Huntington's and Parkinson's and the prion encephalopathies. A family of proteins, known as the serpins, also forms large stable multimers by ordered beta-sheet linkages leading to intracellular accretion and disease. These 'serpinopathies' include early-onset dementia caused by mutations in neuroserpin, liver cirrhosis and emphysema caused by mutations in alpha(1)-antitrypsin (alpha(1)AT), and thrombosis caused by mutations in antithrombin. Serpin structure and function are quite well understood, and the family has therefore become a model system for understanding the beta-sheet expansion disorders collectively known as the conformational diseases. To develop strategies to prevent and reverse these disorders, it is necessary to determine the structural basis of the intermolecular linkage and of the pathogenic monomeric state. Here we report the crystallographic structure of a stable serpin dimer which reveals a domain swap of more than 50 residues, including two long antiparallel beta-strands inserting in the centre of the principal beta-sheet of the neighbouring monomer. This structure explains the extreme stability of serpin polymers, the molecular basis of their rapid propagation, and provides critical new insights into the structural changes which initiate irreversible beta-sheet expansion.
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PMID:Crystal structure of a stable dimer reveals the molecular basis of serpin polymerization. 1897 12

Prion diseases are a group of neurodegenerative diseases associated with the misfolding of the cellular prion protein (PrPC) into the infectious form (PrPSc). There are currently no treatments for prion disease. Bile acids have the ability to protect hepatocytes from apoptosis and are neuroprotective in animal models of other protein-folding neurodegenerative diseases, including Huntington's, Parkinson's, and Alzheimer's disease. Importantly, bile acids are approved for clinical use in patients with cirrhosis and have recently been shown to be safe and possibly effective in pilot trials of patients with amyotrophic lateral sclerosis (ALS). We previously reported that the bile acid ursodeoxycholic acid (UDCA), given early in disease, prolonged incubation periods in male RML-infected mice. Here, we expand on this result to include tauro-ursodeoxycholic acid (TUDCA) treatment trials and delayed UDCA treatment. We demonstrate that despite a high dose of TUDCA given early in disease, there was no significant difference in incubation periods between treated and untreated cohorts, regardless of sex. In addition, delayed treatment with a high dose of UDCA resulted in a significant shortening of the average survival time for both male and female mice compared to their sex-matched controls, with evidence of increased BiP, a marker of apoptosis, in treated female mice. Our findings suggest that treatment with high-dose TUDCA provides no therapeutic benefit and that delayed treatment with high-dose UDCA is ineffective and could worsen outcomes.
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PMID:High Dose and Delayed Treatment with Bile Acids Ineffective in RML Prion-Infected Mice. 2978 43