Human Neuroserpin (PI12): cDNA Cloning and Chromosomal Localization to 3q26

Schrimpf, Sabine; Bleiker, Andreas J.; Brecevic, Lukrecija; Kozlov, Serguei; Berger, Philipp; Osterwalder, Thomas; Krueger, Stefan; Schinzel, Albert; Sonderegger, P.

doi:10.1006/geno.1996.4514

Cited by 56 publications

(66 citation statements)

References 32 publications

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“…During biosynthesis, neuroserpin is translocated into the ER, where its signal peptide is cleaved and the protein moiety is N-glycosylated. Human neuroserpin has three potential N-glycosylation sites within its amino acid sequence (26). Core glycans are trimmed and further processed in the Golgi complex, resulting in a further increase in molecular mass.…”

Section: Mutant Syracuse and Portland Neuroserpin Accumulate Within Tmentioning

confidence: 99%

Mutants of Neuroserpin That Cause Dementia Accumulate as Polymers within the Endoplasmic Reticulum

Miranda

Römisch

Lomas

2004

Journal of Biological Chemistry

104

145

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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.Neuroserpin is a member of the serpin superfamily and is predominantly expressed by neurons of the developing and adult brain. This serpin is secreted from the axonal growth cones of the central and peripheral nervous system, where it inhibits the enzyme tissue plasminogen activator (1-5). The expression pattern of neuroserpin and its in vitro inhibitory activity implicate this serpin in regulating axonal growth, reducing seizure activity, controlling damage in cerebral infarction, and regulating emotional behavior and memory (6 -10).We have recently described an autosomal dominant dementia, familial encephalopathy with neuroserpin inclusion bodies (FENIB), 1 that is characterized by inclusions of mutant neuroserpin within cortical and subcortical neurons (11-13). This dementia is unusual in that the inclusions result from the retention of ordered polymers of neuroserpin, most likely within the endoplasmic reticulum (ER) of neurons (11). Moreover, the number of inclusions is directly related to the molecular instability caused by the mutation and inversely proportional to the age of onset of dementia (13). For example, the Syracuse mutation (S49P) causes dementia in middle age, whereas the more severe Portland mutant (S52R) causes more inclusions and an onset of dementia in the early 20s. Polymers of the serpins result from the sequential...

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Section: Mutant Syracuse and Portland Neuroserpin Accumulate Within Tmentioning

confidence: 99%

Mutants of Neuroserpin That Cause Dementia Accumulate as Polymers within the Endoplasmic Reticulum

Miranda

Römisch

Lomas

2004

Journal of Biological Chemistry

104

145

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“…Neuroserpin is an endogenous protease inhibitor that is activity dependent, expressed in neurons in the late stages of neurogenesis during the process of synapse formation, and continues to be expressed in adult brain (30,31). Point mutations in neuroserpin lead to a neurodegenerative disease characterized by adult-onset dementia and progressive cognitive decline with neuroserpin inclusion bodies (32,33).…”

Section: Neuroserpinmentioning

confidence: 99%

Gene Expression of Metabolic Enzymes and a Protease Inhibitor in the Prefrontal Cortex Are Decreased in Schizophrenia

et al. 2004

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Microarray expression studies have reported decreased mRNA expression of histidine triad nucleotide-binding protein (HINT1) and cytosolic malate dehydrogenase (MDH1) in the dorsolateral prefrontal cortex (DLPFC) of individuals with schizophrenia. Microarray results for neuroserpin (SERPINI1) mRNA in the DLPFC have reported increased and decreased expression in individuals with schizophrenia. The relative abundances of HINT1, MDH1, and SERPINI1 mRNA in the DLPFC in individuals with schizophrenia and controls were measured by real-time quantitative polymerase chain reaction (Q-PCR) and for HINT1 expression by in situ hybridization. The Q-PCR results were compared by analysis of covariance between individuals with schizophrenia and controls. Gene expression levels for HINT1, MDH1, and SERPINI1 were significantly different between the groups. The male individuals with schizophrenia compared to male controls showed reductions by 2.8-to 3.7-fold of HINT1, neuroserpin, and MDH1 by Q-PCR. The decreases in mRNA abundance for MDH1 (P ϭ 0.006), HINT1 (P ϭ 0.050), and neuroserpin (P ϭ 0.005) in DLPFC of male individuals with schizophrenia is consistent with prior reports. HINT1 mRNA was reduced significantly by 34% in layer VI. Though there were no significant interactions with gender, gene expression between female patients and the female control group did not differ. These results confirm earlier reports and suggest abnormalities of specific genes related to metabolic and protease activities in the DLPFC might be considered as part of a molecular pathway in male patients with schizophrenia.

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“…Spn4 was initially identified as one of six serpins expressed in Drosophila oocytes (Han et al, 2000) and is the closest Drosophila homolog to neuroserpin, a vertebrate neuronal serpin (Osterwalder et al, 1996;Schrimpf et al, 1997). We analyzed the Spn4 gene and describe two of its alternative splice isoforms, referred to as Spn4.1 and Spn4.2.…”

Section: Introductionmentioning

confidence: 99%

DrosophilaSerpin 4 Functions as a Neuroserpin-Like Inhibitor of Subtilisin-Like Proprotein Convertases

Osterwalder

Kuhnen²,

Leiserson³

et al. 2004

J. Neurosci.

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The proteolytic processing of neuropeptide precursors is believed to be regulated by serine proteinase inhibitors, or serpins. Here we describe the molecular cloning and functional expression of a novel member of the serpin family, Serine protease inhibitor 4 (Spn4), that we propose is involved in the regulation of peptide maturation in Drosophila. The Spn4 gene encodes at least two different serpin proteins, generated by alternate splicing of the last coding exon. The closest vertebrate homolog to Spn4 is neuroserpin. Like neuroserpin, one of the Spn4 proteins (Spn4.1) features a unique C-terminal extension, reminiscent of an endoplasmic reticulum (ER) retention signal; however, Spn4.1 and neuroserpin have divergent reactive site loops, with Spn4.1 showing a generic recognition site for furin/SPC1, the founding member of the intracellularly active family of subtilisin-like proprotein convertases (SPCs). In vitro, Spn4.1 forms SDS-stable complexes with the SPC furin and directly inhibits it. When Spn4.1 is overexpressed in specific peptidergic cells of Drosophila larvae, the animals exhibit a phenotype consistent with disrupted neuropeptide processing. This observation, together with the unique combination of an ER-retention signal, a target sequence for SPCs in the reactive site loop, and the in vitro inhibitory activity against furin, strongly suggests that Spn4.1 is an intracellular regulator of SPCs.

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Human Neuroserpin (PI12): cDNA Cloning and Chromosomal Localization to 3q26

Cited by 56 publications

References 32 publications

Mutants of Neuroserpin That Cause Dementia Accumulate as Polymers within the Endoplasmic Reticulum

Mutants of Neuroserpin That Cause Dementia Accumulate as Polymers within the Endoplasmic Reticulum

Gene Expression of Metabolic Enzymes and a Protease Inhibitor in the Prefrontal Cortex Are Decreased in Schizophrenia

DrosophilaSerpin 4 Functions as a Neuroserpin-Like Inhibitor of Subtilisin-Like Proprotein Convertases

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