Disease relevance of SERPINI1

• To clarify this issue, we investigated five families with typical neuroserpin inclusion bodies but with various neurological manifestations [1].
• Immunostaining revealed that MCAO resulted in reduction of neuroserpin immunoreactivity in the ipsilateral hemisphere after 2 to 6 hours of ischemia [2].
• However, treatment with neuroserpin in combination with tPA significantly (P<0.05) reduced BBB leakage, brain edema, and ischemic lesion volume compared with rats treated with tPA alone, although ischemic lesion volumes were the same in both groups before the treatment [2].
• We tested the hypothesis that neuroserpin, a natural inhibitor of tPA, reduces tPA-induced neuronal toxicity and increases its therapeutic window for treatment of embolic stroke [2].
• As in the other three members whose gene expression is altered during tumorigenesis, PI12 expression was found to be down-regulated in tumor brain tissues and in two brain cancer cell lines: U-87 MG and H4 [3].

Psychiatry related information on SERPINI1

• 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 [4].
• Intracellular protein deposition due to aggregation caused by conformational alteration is the hallmark of a number of neurodegenerative disorders, including Parkinson's disease, tauopathies, Huntington's disease, and familial encephalopathy with neuroserpin inclusion bodies [5].

High impact information on SERPINI1

• Familial dementia caused by polymerization of mutant neuroserpin [6].
• 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 [6].
• We report the cosegregation of point mutations in the neuroserpin gene (PI12) with the disease in two families [6].
• Recent structural findings show how cytotoxicity can result from even minor changes in conformation that do not lead to amyloid formation, as with the accumulation within the endoplasmic reticulum of intact mutant alpha-1-antitrypsin in hepatocytes and of neuroserpin in neurons [7].
• FINDINGS: Each of the families was heterozygous for an amino acid substitution that affected the conformational stability of neuroserpin [1].

Chemical compound and disease context of SERPINI1

• We show here that glycerol, the sugar alcohol erythritol, the disaccharide trehalose and its breakdown product glucose reduce the rate of polymerization of wild-type neuroserpin and the Ser49Pro mutant that causes dementia [8].

Biological context of SERPINI1

• A cDNA clone for the serine proteinase inhibitor (serpin), neuroserpin, was isolated from a human whole brain cDNA library, and recombinant protein was expressed in insect cells [9].
• Taken together, these data suggest that neuroserpin is likely to be a critical regulator of tPA activity in the central nervous system, and as such may play an important role in neuronal plasticity and/or maintenance [9].
• 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 [10].
• The human and the chicken neuroserpin exhibit an amino acid sequence identity of 80% [11].
• The open reading frame of the cDNA of human neuroserpin, like that of its chicken counterpart, encodes a protein of 410 amino acids [11].

Anatomical context of SERPINI1

• Neuroserpin: a selective inhibitor of tissue-type plasminogen activator in the central nervous system [4].
• 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 [4].
• 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 [10].
• 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 [10].
• Neuroserpin regulates neurite outgrowth in nerve growth factor-treated PC12 cells [12].

Associations of SERPINI1 with chemical compounds

• 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 [4].
• DNA sequence analysis of exons 2 to 9 of the neuroserpin gene in the proband showed the published normal neuroserpin sequence except for the presence of both adenine and cytosine at the first position of codon 52, that indicates heterozygosity for both the normal Ser(AGT) and variant Arg(CGT) at this position in the expressed protein [13].
• Using real-time quantitative PCR, we demonstrated increased neuroserpin mRNA expression in rat frontal cortex after chronic treatment with several classes of antidepressants, including imipramine, fluoxetine, sertraline, and venlafaxine [14].

Regulatory relationships of SERPINI1

• In the central nervous system, neuroserpin (NSP) is a serpin thought to regulate t-PA enzymatic activity [15].

Other interactions of SERPINI1

• The decreases in mRNA abundance for MDH1 (P = 0.006), HINT1 (P = 0.050), and neuroserpin (P = 0.005) in DLPFC of male individuals with schizophrenia is consistent with prior reports [16].
• 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 [17].
• These data provide an alternative method for the inactivation of mutant neuroserpin as a proteinase inhibitor in FENIB and demonstrate a second pathway for the formation of intracellular polymers in association with disease [18].
• Neuroserpin is a novel serine protease inhibitor of the serpin family [11].
• Neuroserpin Portland (Ser52Arg) is trapped as an inactive intermediate that rapidly forms polymers: implications for the epilepsy seen in the dementia FENIB [19].

Analytical, diagnostic and therapeutic context of SERPINI1

• 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 [20].
• Expression and activity profiling of tPA and neuroserpin were performed by immunohistochemistry, in situ hybridization, immunocapture and zymography assays [21].
• By fluorescence in situ hybridization the human neuroserpin gene (HGMW-approved symbol PI12) was mapped to region q26 of chromosome 3 [11].
• Northern blot analysis of human organs demonstrated predominant expression of neuroserpin in the brain [11].
• Our present data suggests that higher neuroserpin expression may predict an unfavorable outcome after radical prostatectomy or hormone therapy [22].

References