ライフサイエンスコーパス: neuroserpin

1 rol biosynthesis and the clearance of mutant neuroserpin.

2 y by polymers of the neuron-specific serpin, neuroserpin.

3 and molecular-dynamics simulations on human neuroserpin.

4 0A mutation suppresses these fluctuations in neuroserpin.

5 The closest vertebrate homolog to Spn4 is neuroserpin.

6 und in patients with the Portland variant of neuroserpin.

7 ly regulated by protease inhibitors, such as neuroserpin.

8 erized by intraneuronal inclusions of mutant neuroserpin.

9 hat affected the conformational stability of neuroserpin.

10 bout the trafficking of wild type and mutant neuroserpins.

11 Neuroserpin (20 micro L of 16 micro mol/L active neurose

12 and have a surprisingly simple composition; neuroserpin (a serine protease inhibitor) is their predo

13 campi, and unilateral treatment of rats with neuroserpin, a natural inhibitor of tPA in the brain, en

14 We tested the hypothesis that neuroserpin, a natural inhibitor of tPA, reduces tPA-ind

15 E2 ligase and Hrd1 E3 ligase while truncated neuroserpin, a protein that lacks 132 amino acids, is de

16 Neuroserpin, a recently identified inhibitor of tissue-t

17 n activator inhibitor-1 (PAI-1) but not with neuroserpin, a tPA-specific inhibitor concentrated in gr

18 Neither the wild-type nor S49P neuroserpin accepted the P7-P2 alpha(1)-anti-trypsin or

19 Administration of neuroserpin after stroke is neuroprotective, seemingly b

20 confirmed that the inclusions were formed of neuroserpin aggregates, and the responsible mutations in

21 Neuroserpin also attenuated kainic acid-induced neuronal

22 Neuroserpin also decreased apoptotic cell counts in the

23 Neuroserpin also effectively inhibited trypsin and nerve

24 onoclonal antibodies that detect polymerized neuroserpin and have used COS-7 cells, stably transfecte

25 ification, and characterization of wild-type neuroserpin and neuroserpin containing the S49P mutation

26 We found that both active neuroserpin and neuroserpin.tPA complexes were internali

27 ss high levels of anti-PA serpins, including neuroserpin and serpin B2, to prevent plasmin generation

28 l model to study the processing of wild type neuroserpin and the Syracuse (S49P) and Portland (S52R)

29 or (tPA) and the serine proteinase inhibitor neuroserpin are both expressed in areas of the brain wit

30 Mechanisms regulating neuroserpin are not known, and the current studies were

31 Mutants of neuroserpin are retained as polymers within the endoplas

32 Here we show that Syracuse and Portland neuroserpin are retained soon after their synthesis in t

33 haracterized by the retention of polymers of neuroserpin as inclusions within the endoplasmic reticul

34 r the LRP-mediated internalization of active neuroserpin, but could not rule out the possibility that

35 to define the cellular pathways involved in neuroserpin catabolism.

36 Moreover, mutant neuroserpin causes locomotor deficits in the fly allowin

37 haracterization of wild-type neuroserpin and neuroserpin containing the S49P mutation that causes FEN

38 r either treatment with or overexpression of neuroserpin decreases the volume of the ischemic lesion

39 Injection of neuroserpin directly into the brain immediately after in

40 In the present study neuroserpin expression and its potential therapeutic ben

41 occlusion (MCAO) increases tPA activity and neuroserpin expression in ischemic tissue, and genetic d

42 to sublethal hypoxia/ischemia increases the neuroserpin expression in the hippocampal CA1 layer and

43 Neuroserpin expression increased in neurons surrounding

44 Wild-type neuroserpin formed SDS-stable complexes with tPA with an

45 In contrast, S49P neuroserpin formed unstable complexes with an associatio

46 sociated proteases capable of binding active neuroserpin functions in this capacity.

47 ic pathway in cells that express polymers of neuroserpin (G392E).

48 the cosegregation of point mutations in the neuroserpin gene (PI12) with the disease in two families

49 oserpin were identified by sequencing of the neuroserpin gene (SERPINI1) in DNA from blood samples or

50 DNA sequence analysis of exons 2 to 9 of the neuroserpin gene in the proband showed the published nor

51 sts that FENIB is caused by mutations in the neuroserpin gene, resulting in intracellular accumulatio

52 (FENIB) is caused by point mutations in the neuroserpin gene.

53 sment by circular dichroism showed that S49P neuroserpin had a lower melting temperature than wild-ty

54 Hydrogen exchange indicates that neuroserpin has greater flexibility in the breach region

55 m (ER) retention signal; however, Spn4.1 and neuroserpin have divergent reactive site loops, with Spn

56 revealed that MCAO resulted in reduction of neuroserpin immunoreactivity in the ipsilateral hemisphe

57 Ischemic brains were treated with neuroserpin in combination with recombinant human tPA (n

58 However, treatment with neuroserpin in combination with tPA significantly (P<0.0

59 pathway, reduced the ubiquitination of G392E neuroserpin in our cell lines and increased the retentio

60 hways, whereas the accumulation of polymeric neuroserpin in the neuronal ER triggers a poorly underst

61 Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is an autosomal dom

62 Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is an autosomal dom

63 The dementia familial encephalopathy with neuroserpin inclusion bodies (FENIB) is caused by point

64 The dementia familial encephalopathy with neuroserpin inclusion bodies (FENIB) is caused by the ac

65 disease entity-familial encephalopathy with neuroserpin inclusion bodies (FENIB).

66 , we investigated five families with typical neuroserpin inclusion bodies but with various neurologic

67 minant dementia familial encephalopathy with neuroserpin inclusion bodies or FENIB.

68 a new disease, familial encephalopathy with neuroserpin inclusion bodies, characterized clinically a

69 n diseases, and familial encephalopathy with neuroserpin inclusion bodies.

70 dementia after age 45 years, and presence of neuroserpin inclusions in only a few neurons.

71 ined and the topographic distribution of the neuroserpin inclusions plotted.

72 mpal CA1 layer and cerebral cortex, and that neuroserpin induces ischemic tolerance and decreases the

73 In vitro studies show that neuroserpin inhibits tPA and, to a lesser extent, urokin

74 indicating the requirement of a cofactor for neuroserpin internalization.

75 ther known plasminogen activator inhibitors, neuroserpin is a more effective inactivator of tPA than

76 n together, these data demonstrate that S49P neuroserpin is a poor proteinase inhibitor and readily f

77 Neuroserpin is a regulator of neuronal growth and plasti

78 indicate that the neuroprotective effect of neuroserpin is due to inhibition of plasmin-mediated exc

79 Surprisingly, despite the fact that active neuroserpin is internalized by LRP, this form of the mol

80 Taken together, these data suggest that neuroserpin is likely to be a critical regulator of tPA

81 Mutant neuroserpin is retained within the endoplasmic reticulum

82 Neuroserpin isolated from inclusion bodies in the brain

83 In summary, neuroserpin levels appear to be carefully regulated by L

84 early-onset dementia caused by mutations in neuroserpin, liver cirrhosis and emphysema caused by mut

85 Thus, neuroserpin may be a naturally occurring neuroprotective

86 tion between the reactive centre loop of one neuroserpin molecule with beta-sheet A of the next.

87 and thrombotic proteases, whereas mammalian neuroserpin (NSP) inhibits only thrombolytic proteases.

88 In the central nervous system, neuroserpin (NSP) is a serpin thought to regulate t-PA e

89 her than plasminogen and that the effects of neuroserpin on seizure progression and neuronal cell sur

90 Like neuroserpin, one of the Spn4 proteins (Spn4.1) features

91 eath, and this effect is abrogated by either neuroserpin or the NMDA receptor antagonist MK-801.

92 dings provide strong support for the role of neuroserpin polymerization in the formation of the intra

93 ur cell lines and increased the retention of neuroserpin polymers in both HeLa cells and primary neur

94 ase-causing mutation and the accumulation of neuroserpin polymers in cell and fly models of the disea

95 We show here that neuroserpin Portland (Ser52Arg), which causes a severe f

96 in keeping with the reactive centre loop of neuroserpin Portland being partially inserted into beta-

97 everity of dementia in FENIB associated with neuroserpin Portland.

98 otein consisted of residues 20 to 410 of the neuroserpin precursor deduced from its cDNA sequence ind

99 The increased mobility of these regions in neuroserpin relative to alpha(1)-antitrypsin provides a

100 The degradation of G392E neuroserpin results from SREBP-dependent activation of t

101 xin-induced cell death and is independent of neuroserpin's ability to inhibit tPA activity.

102 to alpha(1)-antitrypsin provides a basis for neuroserpin's increased tendency toward the formation of

103 ese findings have led to the hypothesis that neuroserpin's neuroprotection is mediated by inhibition

104 e in the proband showed the published normal neuroserpin sequence except for the presence of both ade

105 ion and that intracerebral administration of neuroserpin significantly reduced this proteolysis.

106 An affinity-purified antibody against neuroserpin specifically labels the Collins bodies, conf

107 ellular handling of all four mutant forms of neuroserpin that cause FENIB.

108 hila models to show that the G392E mutant of neuroserpin that forms polymers is degraded by UBE2j1 E2

109 ttern of seizure spreading and a response to neuroserpin that is similar to that of wild-type animals

110 We found that both active neuroserpin and neuroserpin.tPA complexes were internalized by mouse cor

111 d uPA activity were significantly reduced in neuroserpin-treated animals.

112 re progression is significantly delayed, and neuroserpin treatment does not further delay seizure spr

113 Inhibition of tPA within the hippocampus by neuroserpin treatment does not prevent seizure onset but

114 Like other members of the serpin family, neuroserpin undergoes a large conformational change as p

115 Ser52 was found indicating that only mutant neuroserpin was present in the inclusion bodies.

116 oserpin (20 micro L of 16 micro mol/L active neuroserpin) was intracisternally injected 3 hours and t

117 or the serine proteinase inhibitor (serpin), neuroserpin, was isolated from a human whole brain cDNA

118 aggregates, and the responsible mutations in neuroserpin were identified by sequencing of the neurose

119 Both mutant and wild type neuroserpin were partially degraded by proteasomes.

120 rages 4.6 A but becomes as large as 7.5 A in neuroserpin while it remains stable at approximately 3.5

121 elix F away from the face of beta-sheet A in neuroserpin while no such movement is evident in alpha(1

122 pins such as alpha(1)-antitrypsin, wild-type neuroserpin will polymerize under near-physiological con

123 Chemical characterization of the variant neuroserpin will significantly enhance the understanding

124 pha(1)-antitrypsin within hepatocytes and of neuroserpin within neurons to cause cirrhosis and dement

125 NIB) is caused by the accumulation of mutant neuroserpin within neurons, but little is known about th