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 compa...Continue Reading
Repair of the secretion defect in the Z form of alpha 1-antitrypsin by addition of a second mutation
Inhibition of proteasome activities and subunit-specific amino-terminal threonine modification by lactacystin
The endoplasmic reticulum degradation pathway for mutant secretory proteins alpha1-antitrypsin Z and S is distinct from that for an unassembled membrane protein.
Degradation of a mutant secretory protein, alpha1-antitrypsin Z, in the endoplasmic reticulum requires proteasome activity.
Proteasome-dependent endoplasmic reticulum-associated protein degradation: an unconventional route to a familiar fate
Neuroserpin, a brain-associated inhibitor of tissue plasminogen activator is localized primarily in neurons. Implications for the regulation of motor learning and neuronal survival.
The axonally secreted serine proteinase inhibitor, neuroserpin, inhibits plasminogen activators and plasmin but not thrombin.
Chemical chaperones mediate increased secretion of mutant alpha 1-antitrypsin (alpha 1-AT) Z: A potential pharmacological strategy for prevention of liver injury and emphysema in alpha 1-AT deficiency
Processing by endoplasmic reticulum mannosidases partitions a secretion-impaired glycoprotein into distinct disposal pathways
Retention of mutant alpha(1)-antitrypsin Z in endoplasmic reticulum is associated with an autophagic response
The proteasome participates in degradation of mutant alpha 1-antitrypsin Z in the endoplasmic reticulum of hepatoma-derived hepatocytes
6-mer peptide selectively anneals to a pathogenic serpin conformation and blocks polymerization. Implications for the prevention of Z alpha(1)-antitrypsin-related cirrhosis
Mutant Neuroserpin (S49P) that causes familial encephalopathy with neuroserpin inclusion bodies is a poor proteinase inhibitor and readily forms polymers in vitro.
Acyl-enzyme complexes between tissue-type plasminogen activator and neuroserpin are short-lived in vitro.
Intracellular accumulation of antithrombin Morioka (C95R), a novel mutation causing type I antithrombin deficiency
Expression and functional characterization of the serine protease inhibitor neuroserpin in endocrine cells
Serpin polymerization is prevented by a hydrogen bond network that is centered on his-334 and stabilized by glycerol.
Elucidation of the molecular logic by which misfolded alpha 1-antitrypsin is preferentially selected for degradation
Impaired explorative behavior and neophobia in genetically modified mice lacking or overexpressing the extracellular serine protease inhibitor neuroserpin
Alpha-1 antitrypsin deficiency: a conformational disease associated with lung and liver manifestations
Neuroserpin polymers activate NF-kappaB by a calcium signaling pathway that is independent of the unfolded protein response.
Endoplasmic reticulum-associated degradation (ERAD) and autophagy cooperate to degrade polymerogenic mutant serpins.
The endoplasmic reticulum (ER)-associated degradation system regulates aggregation and degradation of mutant neuroserpin.
Sequestration of mutated alpha1-antitrypsin into inclusion bodies is a cell-protective mechanism to maintain endoplasmic reticulum function.
The intracellular accumulation of polymeric neuroserpin explains the severity of the dementia FENIB.
Sterol metabolism regulates neuroserpin polymer degradation in the absence of the unfolded protein response in the dementia FENIB
Hepatic fibrosis and carcinogenesis in α1-antitrypsin deficiency: a prototype for chronic tissue damage in gain-of-function disorders
Neuroserpin Portland (Ser52Arg) is trapped as an inactive intermediate that rapidly forms polymers: implications for the epilepsy seen in the dementia FENIB
Two non-homologous brain diseases-related genes, SERPINI1 and PDCD10, are tightly linked by an asymmetric bidirectional promoter in an evolutionarily conserved manner
Association between neuroserpin and molecular markers of brain damage in patients with acute ischemic stroke.
Three new alpha1-antitrypsin deficiency variants help to define a C-terminal region regulating conformational change and polymerization.
AAV-mediated overexpression of neuroserpin in the hippocampus decreases PSD-95 expression but does not affect hippocampal-dependent learning and memory
Interactions between N-linked glycosylation and polymerisation of neuroserpin within the endoplasmic reticulum
The stability and activity of human neuroserpin are modulated by a salt bridge that stabilises the reactive centre loop
Sugar and alcohol molecules provide a therapeutic strategy for the serpinopathies that cause dementia and cirrhosis
A novel monoclonal antibody to characterize pathogenic polymers in liver disease associated with alpha1-antitrypsin deficiency.
Encephalopathy with neuroserpin inclusion bodies presenting as progressive myoclonus epilepsy and associated with a novel mutation in the Proteinase Inhibitor 12 gene
pH-dependent stability of neuroserpin is mediated by histidines 119 and 138; implications for the control of beta-sheet A and polymerization.
Accumulation of mutant neuroserpin precedes development of clinical symptoms in familial encephalopathy with neuroserpin inclusion bodies
Probing neuroserpin polymerization and interaction with amyloid-beta peptides using single molecule fluorescence.
Functional and dysfunctional conformers of human neuroserpin characterized by optical spectroscopies and Molecular Dynamics
Crystallographic and cellular characterisation of two mechanisms stabilising the native fold of alpha1-antitrypsin: implications for disease and drug design.
Lectin OS-9 delivers mutant neuroserpin to endoplasmic reticulum associated degradation in familial encephalopathy with neuroserpin inclusion bodies
The pathological Trento variant of alpha-1-antitrypsin (E75V) shows nonclassical behaviour during polymerization.
Inhibition of proteasome by bortezomib causes intracellular aggregation of hepatic serpins and increases the latent circulating form of antithrombin
Dominant-negative SERPING1 variants cause intracellular retention of C1 inhibitor in hereditary angioedema
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