Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0085584 (encephalopathy)
 18,178 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aberrant protein processing with tissue deposition is associated with many common neurodegenerative disorders; however, the complex interplay of genetic and environmental factors has made it difficult to decipher the sequence of events linking protein aggregation with clinical disease. Substantial progress has been made toward understanding the pathophysiology of prototypical conformational diseases and protein polymerization in the superfamily of serine proteinase inhibitors (serpins). Here we describe a new disease, familial encephalopathy with neuroserpin inclusion bodies, characterized clinically as an autosomal dominantly inherited dementia, histologically by unique neuronal inclusion bodies and biochemically by polymers of the neuron-specific serpin, neuroserpin. We report the cosegregation of point mutations in the neuroserpin gene (PI12) with the disease in two families. The significance of one mutation, S49P, is evident from its homology to a previously described serpin mutations, whereas that of the other, S52R, is predicted by modelling of the serpin template. Our findings provide a molecular mechanism for a familial dementia and imply that inhibitors of protein polymerization may be effective therapies for this disorder and perhaps for other more common neurodegenerative diseases.
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PMID:Familial dementia caused by polymerization of mutant neuroserpin. 1051 35

We report on a new familial neurodegenerative disease with associated dementia that has presented clinically in the fifth decade, in both genders, and in each of several generations of a large family from New York State-a pattern of inheritance consistent with an autosomal dominant mode of transmission. A key pathological finding is the presence of neuronal inclusion bodies distributed throughout the gray matter of the cerebral cortex and in certain subcortical nuclei. These inclusions are distinct from any described previously and henceforth are identified as Collins bodies. The Collins bodies can be isolated by simple biochemical procedures and have a surprisingly simple composition; neuroserpin (a serine protease inhibitor) is their predominant component. An affinity-purified antibody against neuroserpin specifically labels the Collins bodies, confirming their chemical composition. Therefore, we propose a new disease entity-familial encephalopathy with neuroserpin inclusion bodies (FENIB). The conclusion that FENIB is a previously unrecognized neurodegenerative disease is supported by finding Collins bodies in a small kindred from Oregon with familial dementia who are unrelated to the New York family. The autosomal dominant inheritance strongly suggests that FENIB is caused by mutations in the neuroserpin gene, resulting in intracellular accumulation of the mutant protein.
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PMID:Familial encephalopathy with neuroserpin inclusion bodies. 1059 21

Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is an autosomal dominant dementia that is characterized by intraneuronal inclusions of mutant neuroserpin. We report here the expression, purification, and characterization of wild-type neuroserpin and neuroserpin containing the S49P mutation that causes FENIB. Wild-type neuroserpin formed SDS-stable complexes with tPA with an association rate constant and K(i) of 1.2 x 10(4) m(-1) s(-1) and 5.8 nm, respectively. In contrast, S49P neuroserpin formed unstable complexes with an association rate constant and K(i) of 0.3 x 10(4) m(-1) s(-1) and 533.3 nm, respectively. An assessment by circular dichroism showed that S49P neuroserpin had a lower melting temperature than wild-type protein (49.9 and 56.6 degrees C, respectively) and more readily formed loop-sheet polymers under physiological conditions. Neither the wild-type nor S49P neuroserpin accepted the P7-P2 alpha(1)-anti-trypsin or P14-P3 antithrombin-reactive loop peptides that have been shown to block polymer formation in other members of the serpin superfamily. Taken together, these data demonstrate that S49P neuroserpin is a poor proteinase inhibitor and readily forms loop-sheet polymers. These findings provide strong support for the role of neuroserpin polymerization in the formation of the intraneuronal inclusions that are characteristic of FENIB.
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PMID:Mutant Neuroserpin (S49P) that causes familial encephalopathy with neuroserpin inclusion bodies is a poor proteinase inhibitor and readily forms polymers in vitro. 1188 Mar 76

Neuroserpin is an axonally secreted serine protease inhibitor expressed in the nervous system that protects neurons from ischemia-induced apoptosis. Mutant neuroserpin forms have been found polymerized in inclusion bodies in a familial autosomal encephalopathy causing dementia, or associated with epilepsy. Regulation of neuroserpin expression is mostly unknown. Here we demonstrate that neuroserpin mRNA and the RNA-binding protein HuD are co-expressed in the rat central nervous system, and that HuD binds neuroserpin mRNA in vitro with high affinity. Gel-shift, supershift and T1 RNase assays revealed three HuD-binding sequences in the 3'-untranslated region (3'-UTR) of neuroserpin mRNA. They are AU-rich and 20, 51 and 19 nt in length. HuD binding to neuroserpin mRNA was also demonstrated in extracts of PC12 pheochromocytoma cells. Additionally, ectopic expression of increasing amounts of HuD in these cells results in the accumulation of neuroserpin 3'-UTR mRNA. Furthermore, stably transfected PC12 cells over-expressing HuD contain increased levels of both neuroserpin mRNAs (3.0 and 1.6 kb) and protein. Our results indicate that HuD stabilizes neuroserpin mRNA by binding to specific AU-rich sequences in its 3'-UTR, which prolongs the mRNA lifetime and increases protein level.
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PMID:HuD binds to three AU-rich sequences in the 3'-UTR of neuroserpin mRNA and promotes the accumulation of neuroserpin mRNA and protein. 1200 Aug 40

Alpha(1)-antitrypsin functions as a "mousetrap" to inhibit its target proteinase, neutrophil elastase. The common severe Z deficiency variant (Glu(342)-->Lys) destabilizes the mousetrap to allow a sequential protein-protein interaction between the reactive-centre loop of one molecule and beta-sheet A of another. These loop-sheet polymers accumulate within hepatocytes to form inclusion bodies that are associated with juvenile cirrhosis and hepatocellular carcinoma. The lack of circulating protein predisposes the Z alpha(1)-antitrypsin homozygote to emphysema. Loop-sheet polymerization is now recognized to underlie deficiency variants of other members of the serine proteinase inhibitor (serpin) superfamily, i.e. antithrombin, C1 esterase inhibitor and alpha(1)-antichymotrypsin, which are associated with thrombosis, angio-oedema and emphysema respectively. Moreover, we have shown recently that the same process in a neuron-specific protein, neuroserpin, underlies a novel inclusion-body dementia, known as familial encephalopathy with neuroserpin inclusion bodies. Our understanding of the structural basis of polymerization has allowed the development of strategies to prevent the aberrant protein-protein interaction in vitro. This must now be achieved in vivo if we are to treat the associated clinical syndromes.
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PMID:Hypersensitive mousetraps, alpha1-antitrypsin deficiency and dementia. 1202 31

Familial conformational diseases occur when a mutation alters the conformation of a protein resulting in abnormal intermolecular interactions, protein aggregation, and consequent tissue damage. The molecular mechanisms of conformational disease are best understood for the serine protease inhibitor (serpin) superfamily of proteins. The serpinopathies include alpha(1)-antitrypsin (SERPINA1) deficiency and the newly characterized familial encephalopathy with neuroserpin inclusion bodies (FENIB) resulting from mutations in the neuroserpin (SERPINI1) gene. This review discusses how insights gained from the study of the serpins may be used to guide our research into other common diseases such as Alzheimer disease, Huntington disease, and Parkinson disease.
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PMID:Familial conformational diseases and dementias. 1211 52

Alpha-1-antitrypsin (alpha(1)-antitrypsin) is the archetypal member of the serine proteinase inhibitor or serpin superfamily. The most common severe deficiency variant is the Z allele, which results in the accumulation of mutant protein within hepatocytes. This 'protein overload' causes neonatal hepatitis, cirrhosis and hepatocellular carcinoma. The lack of circulating plasma alpha(1)-antitrypsin results in early-onset panlobular emphysema. The mechanism underlying the deficiency of Z alpha(1)-antitrypsin is due to an aberrant conformational transition within the protein and the formation of chains of polymers that tangle within the secretory pathway of hepatocytes. This mechanism also underlies the plasma deficiency of other members of the serpin superfamily to cause a class of diseases called the serpinopathies. Specifically mutant alleles of antithrombin, C1-inhibitor and alpha(1)-antichymotrypsin have been reported that favour the spontaneous formation of polymers and the retention of protein within hepatocytes. The consequent lack of plasma antithrombin, C1-inhibitor and alpha(1)-antichymotrypsin results in thrombosis, angio-oedema and emphysema, respectively. Moreover, the polymerisation of mutants of neuroserpin results in the retention of polymers within neurones to cause the inclusion body dementia, familial encephalopathy with neuroserpin inclusion bodies or FENIB. We review here the genetic and molecular basis and clinical features of alpha(1)-antitrypsin deficiency, and show how this provides a platform to understand the other serpinopathies.
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PMID:Practical genetics: alpha-1-antitrypsin deficiency and the serpinopathies. 1469 55

Neuroserpin is a member of the serine proteinase inhibitor (serpin) gene family that reacts preferentially with tissue-type plasminogen activator (tPA) and is primarily localized to neurons in regions of the brain where tPA is also found. Outside of the central nervous system (CNS) tPA is predominantly found in the blood where its primary function is as a thrombolytic enzyme. However, tPA is also expressed within the CNS where it has a very different function, promoting events associated not only with synaptic plasticity but also with cell death in a number of settings, such as cerebral ischemia and seizures. Neuroserpin is released from neurons in response to neuronal depolarization and plays an important role in the development of synaptic plasticity. Following the onset of cerebral ischemia there is an increase in both tPA activity and neuroserpin expression in the area surrounding the necrotic core (ischemic penumbra), and treatment with neuroserpin following ischemic stroke or overexpression of the neuroserpin gene results in a significant decrease in the volume of the ischemic area as well as in the number of apoptotic cells. TPA activity and neuroserpin expression are also increased in specific areas of the brain by seizures, and treatment with neuroserpin slows the progression of seizure activity throughout the CNS and results in significant neuronal survival in the hippocampus. Mutations in human neuroserpin result in a form of autosomal dominant inherited dementia which is characterized by the presence of intraneuronal inclusion bodies and is known as Familial Encephalopathy with Neuroserpin Inclusion Bodies.
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PMID:Neuroserpin: a selective inhibitor of tissue-type plasminogen activator in the central nervous system. 1498 20

The dementia familial encephalopathy with neuroserpin inclusion bodies (FENIB) is caused by the accumulation of mutant neuroserpin within neurons (Davis, R. L., Shrimpton, A. E., Holohan, P. D., Bradshaw, C., Feiglin, D., Sonderegger, P., Kinter, J., Becker, L. M., Lacbawan, F., Krasnewich, D., Muenke, M., Lawrence, D. A., Yerby, M. S., Shaw, C.-M., Gooptu, B., Elliott, P. R., Finch, J. T., Carrell, R. W., and Lomas, D. A. (1999) Nature 401, 376-379), but little is known about the trafficking of wild type and mutant neuroserpins. We have established a cell model to study the processing of wild type neuroserpin and the Syracuse (S49P) and Portland (S52R) mutants that cause FENIB. Here we show that Syracuse and Portland neuroserpin are retained soon after their synthesis in the endoplasmic reticulum and that the limiting step in their processing is the transport to the Golgi complex. This is in contrast to the wild type protein, which is secreted into the culture medium. Mutant neuroserpin is retained within the endoplasmic reticulum as polymers, similar to those isolated from the intraneuronal inclusions in the brains of individuals with FENIB. Remarkably, the Portland mutant showed faster accumulation and slower secretion compared with the Syracuse mutant, in keeping with the more severe clinical phenotype found in patients with the Portland variant of neuroserpin. Both mutant and wild type neuroserpin were partially degraded by proteasomes. Taken together, our results provide further understanding of how cells handle defective but ordered mutant proteins and provide strong support for a common mechanism of disease caused by mutants of the serine protease inhibitor superfamily.
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PMID:Mutants of neuroserpin that cause dementia accumulate as polymers within the endoplasmic reticulum. 1509 May 43

This is an abstract of my lecture on familial non-Alzheimer dementia. 1. Vascular dementia 1) Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by autosomal dominant inheritance, smooth muscle cell degeneration and granular osmiophilic material (GOM) in arterioles, and Notch 3 mutations. 2) CARASIL This is an autosomal recessive vascular dementia with unknown etiology. 3) Familial amyloid angiopathy Familial cerebral hemorrhage and dementia is caused by mutations in amyloid precursor protein, cystatin c, and Bri genes. 2. Familial non-Alzheimer degenerative dementia 1) Dementia with Lewy bodies This is characterized by Alzheimer like dementia, visual hallucination and diffuse Lewy bodies which are formed by ubiquitinated alpha-synuclein. Occasionally, familial forms are reported, but gene mutations are unknown. 2) Frontotemporal dementia (FTD) FTDP-17 is characterized by tau mutations, character and personal changes, and disinhibition. The gene mutations were also found in familial forms of Pick's disease, corticobasal degeneration, and other tauopathies. 3) Familial British dementia (FBD), familial Danish dementia (FDD) FBD and FDD are characterized by Abri amyloid deposits, amyloid angiopathy and dementia. Mutations in Bri gene are reported. 4) Familial encephalopathy with neuroserpin inclusion bodies (FENIB) FENIB is characterized by dementia, Collins body and neuroserpin gene mutation.
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PMID:[Familial non-Alzheimer dementia]. 1515 61


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