scholarly journals Accumulation of Mutant Neuroserpin Precedes Development of Clinical Symptoms in Familial Encephalopathy with Neuroserpin Inclusion Bodies

2007 ◽  
Vol 170 (4) ◽  
pp. 1305-1313 ◽  
Author(s):  
Giovanna Galliciotti ◽  
Markus Glatzel ◽  
Jochen Kinter ◽  
Serguei V. Kozlov ◽  
Paolo Cinelli ◽  
...  
Keyword(s):  
Inclusion Bodies ◽  
Clinical Symptoms ◽  
Familial Encephalopathy

scholarly journals Latent S49P Neuroserpin Forms Polymers in the Dementia Familial Encephalopathy with Neuroserpin Inclusion Bodies

2005 ◽  
Vol 280 (14) ◽  
pp. 13735-13741 ◽  
Author(s):  
Maki Onda ◽  
Didier Belorgey ◽  
Lynda K. Sharp ◽  
David A. Lomas
Keyword(s):  
Inclusion Bodies ◽  
Familial Encephalopathy

scholarly journals Familial Encephalopathy with Neuroserpin Inclusion Bodies

1999 ◽  
Vol 155 (6) ◽  
pp. 1901-1913 ◽  
Author(s):  
Richard L. Davis ◽  
Peter D. Holohan ◽  
Antony E. Shrimpton ◽  
Arthur H. Tatum ◽  
John Daucher ◽  
...  
Keyword(s):  
Inclusion Bodies ◽  
Familial Encephalopathy

Hypersensitive mousetraps, α1-antitrypsin deficiency and dementia

2002 ◽  
Vol 30 (2) ◽  
pp. 89-92 ◽  
Author(s):  
D. A. Lomas ◽  
A. Lourbakos ◽  
S.-A. Cumming ◽  
D. Belorgey
Keyword(s):  
Protein Interaction ◽  
Inclusion Bodies ◽  
Serine Proteinase ◽  
Specific Protein ◽  
Structural Basis ◽  
Protein Protein Interaction ◽  
Antitrypsin Deficiency ◽  
Familial Encephalopathy

α1-Antitrypsin functions as a ‘mousetrap’ to inhibit its target proteinase, neutrophil elastase. The common severe Z deficiency variant (Glu342 → Lys) destabilizes the mousetrap to allow a sequential protein-protein interaction between the reactive-centre loop of one molecule and β-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 α1-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 α1-anti-chymotrypsin, 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.

scholarly journals Neuroserpin: structure, function, physiology and pathology

2021 ◽  
Author(s):  
Emanuela D’Acunto ◽  
Annamaria Fra ◽  
Cristina Visentin ◽  
Mauro Manno ◽  
Stefano Ricagno ◽  
...  
Keyword(s):  
Inclusion Bodies ◽  
Synapse Formation ◽  
Axon Growth ◽  
Serine Protease Inhibitor ◽  
Mechanisms Of Action ◽  
Inhibitory Mechanisms ◽  
Genome Wide ◽  
Familial Encephalopathy ◽  
Critical Revision ◽  
Active Research

AbstractNeuroserpin is a serine protease inhibitor identified in a search for proteins implicated in neuronal axon growth and synapse formation. Since its discovery over 30 years ago, it has been the focus of active research. Many efforts have concentrated in elucidating its neuroprotective role in brain ischemic lesions, the structural bases of neuroserpin conformational change and the effects of neuroserpin polymers that underlie the neurodegenerative disease FENIB (familial encephalopathy with neuroserpin inclusion bodies), but the investigation of the physiological roles of neuroserpin has increased over the last years. In this review, we present an updated and critical revision of the current literature dealing with neuroserpin, covering all aspects of research including the expression and physiological roles of neuroserpin, both inside and outside the nervous system; its inhibitory and non-inhibitory mechanisms of action; the molecular structure of the monomeric and polymeric conformations of neuroserpin, including a detailed description of the polymerisation mechanism; and the involvement of neuroserpin in human disease, with particular emphasis on FENIB. Finally, we briefly discuss the identification by genome-wide screening of novel neuroserpin variants and their possible pathogenicity.

scholarly journals Neuroserpin Inclusion Bodies in a FENIB Yeast Model

2021 ◽  
Vol 9 (7) ◽  
pp. 1498
Author(s):  
Valentina Vapore ◽  
Corrado Mazzaglia ◽  
Diego Sibilia ◽  
Mara Del Vecchio ◽  
Gernot Fruhmann ◽  
...  
Keyword(s):  
Cell Death ◽  
Mammalian Cells ◽  
Inclusion Bodies ◽  
Point Mutations ◽  
Monogenic Disease ◽  
Lag Phase ◽  
Cell Toxicity ◽  
Wild Type ◽  
Familial Encephalopathy ◽  
Human Wild Type

FENIB (familial encephalopathy with neuroserpin inclusion bodies) is a human monogenic disease caused by point mutations in the SERPINI1 gene, characterized by the intracellular deposition of polymers of neuroserpin (NS), which leads to proteotoxicity and cell death. Despite the different cell and animal models developed thus far, the exact mechanism of cell toxicity elicited by NS polymers remains unclear. Here, we report that human wild-type NS and the polymerogenic variant G392E NS form protein aggregates mainly localized within the endoplasmic reticulum (ER) when expressed in the yeast S. cerevisiae. The expression of NS in yeast delayed the exit from the lag phase, suggesting that NS inclusions cause cellular stress. The cells also showed a higher resistance following mild oxidative stress treatments when compared to control cells. Furthermore, the expression of NS in a pro-apoptotic mutant strain-induced cell death during aging. Overall, these data recapitulate phenotypes observed in mammalian cells, thereby validating S. cerevisiae as a model for FENIB.

FAMILIAL ENCEPHALOPATHY WITH NEUROSERPIN INCLUSION BODIES (FENIB)

1999 ◽  
Vol 58 (5) ◽  
pp. 514
Author(s):  
R. L. Davis ◽  
A. H. Tutum ◽  
A. E. Shrimpton ◽  
P. D. Holohan
Keyword(s):  
Inclusion Bodies ◽  
Familial Encephalopathy

scholarly journals A rat model of human FENIB (familial encephalopathy with neuroserpin inclusion bodies)

2006 ◽  
Vol 346 (3) ◽  
pp. 1040-1047 ◽  
Author(s):  
Katsura Takano ◽  
Yasuko Kitao ◽  
Reiko Inagi ◽  
Takashi Momoi ◽  
Tomohiro Matsuyama ◽  
...  
Keyword(s):  
Rat Model ◽  
Inclusion Bodies ◽  
Familial Encephalopathy

scholarly journals Embelin as Lead Compound for New Neuroserpin Polymerization Inhibitors

Life ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 111
Author(s):  
Cristina Visentin ◽  
Loana Musso ◽  
Luca Broggini ◽  
Francesca Bonato ◽  
Rosaria Russo ◽  
...  
Keyword(s):  
Inclusion Bodies ◽  
Point Mutations ◽  
Lead Compound ◽  
Specific Point ◽  
Familial Encephalopathy ◽  
The Central Nervous System ◽  
The One ◽  
Interaction Surface ◽  
Better Than

Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a severe and lethal neurodegenerative disease. Upon specific point mutations in the SERPINI1gene-coding for the human protein neuroserpin (NS) the resulting pathologic NS variants polymerize and accumulate within the endoplasmic reticulum of neurons in the central nervous system. To date, embelin (EMB) is the only known inhibitor of NS polymerization in vitro. This molecule is capable of preventing NS polymerization and dissolving preformed polymers. Here, we show that lowering EMB concentration results in increasing size of NS oligomers in vitro. Moreover, we observe that in cells expressing NS, the polymerization of G392E NS is reduced, but this effect is mediated by an increased proteasomal degradation rather than polymerization impairment. For these reasons we designed a systematic chemical evolution of the EMB scaffold aimed to improve its anti-polymerization properties. The effect of EMB analogs against NS polymerization was assessed in vitro. None of the EMB analogs displayed an anti-polymerization activity better than the one reported for EMB, indicating that the EMB–NS interaction surface is very specific and highly optimized. Thus, our results indicate that EMB is, to date, still the best candidate for developing a treatment against NS polymerization.

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