ライフサイエンスコーパス: FALS

1 f upper motor neuron (UMN) involvement in 10 FALS A4V subjects.

2 We find that all 11 FALS-associated SOD1 mutants examined using this system

3 Analysis of a further 272 FALS cases and 5,510 internal controls confirmed the ove

4 lysis identified 4 mutations in 7 out of 274 FALS cases.

5 vitro aggregation and denaturation of A4V, a FALS-linked variant of SOD1.

6 D can catalyze free radical generation and a FALS mutant, G93A, exhibits an enhanced free radical-gen

7 beta-barrel (H43R) and dimer interface (A4V) FALS mutants reveal reduced stability and drastically in

8 atient and two novel mutations in 2 affected FALS siblings.

9 leads toward effective therapeutics against FALS.

10 es found severe abnormalities of LMNs in all FALS and SALS subjects.

11 ximately 20% of these cases of familial ALS (FALS) are caused by mutations of copper/zinc superoxide

12 -exome analyses of 1,022 index familial ALS (FALS) cases and 7,315 controls.

13 Approximately 20% of familial ALS (FALS) cases are due to known mutations in the copper, zi

14 count for approximately 25% of familial ALS (FALS) cases.

15 In 16 familial ALS (FALS) pedigrees without mutations in SOD1, we failed to

16 c lateral sclerosis (ALS) have familial ALS (FALS), and 20% of FALS are caused by mutations of supero

17 alysis of 363 index cases with familial ALS (FALS).

18 disease, producing 21q linked familial ALS (FALS).

19 al process in sporadic ALS and familial ALS (FALS).

20 LS with dementia (ALS/dementia, n = 10), and FALS (n = 16).

21 d as a mechanism of MN death in both ALS and FALS.

22 e model, previously characterized models and FALS human tissues revealed that the accumulation of det

23 spinal anterior horn neurons in all SALS and FALS cases, except for those with SOD1 mutations.

24 idence for a common pathogenesis of SALS and FALS has remained elusive.

25 nd evaluate potential therapies for SALS and FALS.

26 on step in the pathogenesis between SALS and FALS.

27 Similar studies of the wild type and FALS mutant CuZnSOD holoenzymes in the "as isolated" met

28 ore, crystal structures of SOD wild-type and FALS mutant H43R proteins uncover resulting local framew

29 een loss-of-function (LOF) NEK1 variants and FALS risk.

30 Thus, modifications to the protein, such as FALS mutations, fragmentation and possibly covalent modi

31 hed NSC34 cellular model for SOD1-associated FALS, we investigated the effects of mutant SOD1 specifi

32 s generated from postmortem tissue from both FALS and SALS patients, we show that astrocytes derived

33 ced K+ currents were evident in both c9orf72 FALS and SALS cohorts, and these changes in axonal excit

34 FALS and those with SALS (mean [SD], c9orf72 FALS: 0.50 [0.02] milliseconds; SALS: 0.52 [0.02] millis

35 illiseconds) was also evident in the c9orf72 FALS (P < .05) and SALS (P < .01) cohorts.

36 gnificantly reduced in patients with c9orf72 FALS (1.2% [1.8%]) and sporadic ALS (1.6% [1.2%]) compar

37 udies were taken on 15 patients with c9orf72 FALS and 11 asymptomatic expansion carriers of c9orf72 w

38 tion, were measured in patients with c9orf72 FALS and results were compared with asymptomatic c9orf72

39 antly increased in the patients with c9orf72 FALS and those with SALS (mean [SD], c9orf72 FALS: 0.50

40 10 clinically affected patients with c9orf72 FALS, 9 asymptomatic c9orf72 mutation carriers, and 21 p

41 within the profilin 1 (PFN1) gene can cause FALS.

42 roperty explains why mutations in SOD1 cause FALS has been debated.

43 The fact that some MTSOD1s that cause FALS have full dismutase activity (e.g. G37R) and others

44 vity (e.g. G85R) suggests that MTSOD1 causes FALS due to toxicity of the protein rather than a loss i

45 Using transgenic mice expressing a common FALS-associated FUS mutation (FUS-R521C mice), we found

46 othiols by wild-type (WT) SOD and two common FALS mutants, alanine-4 valine (A4V) SOD and glycine-37

47 ntially toxic gain of function of two common FALS mutations that may contribute to neurodegeneration

48 and biophysical properties of nine different FALS variants of SOD1 polypeptides, including enzymatic

49 ion, the common structural basis for diverse FALS mutations resulting in aggregation is not fully und

50 ild-type SOD1 and three structurally diverse FALS mutants (A4V, G37R, and H46R), we find that a commo

51 r calcineurin activity than cells expressing FALS-related mutant SOD (SODV148G); however, cells expre

52 lateral sclerosis (ALS) cases are familial (FALS), and approximately 25% of FALS cases are caused by

53 Approximately 10% of cases are familial (FALS), typically with a dominant inheritance mode.

54 ut about 5 to 10% of ALS cases are familial (FALS).

55 The human wild-type and five FALS Sod mutant transgenes were introduced into the frui

56 Here we used wild-type (WT) SOD and five FALS-related mutants (G37R, H46R, G85R, D90A, and L144F)

57 cases are sporadic, with the familial form (FALS) representing fewer than 10% of all cases.

58 The most frequent FALS mutation in HSOD, Ala4-->Val, is associated with th

59 underlie the toxic function of the many HSOD FALS mutations.

60 tion of spinal cord motor neurons from human FALS cases, in conjunction with reverse transcriptase-PC

61 severity observed with the A4V patients, if FALS is associated with a differential gain of the free

62 ion and degeneration in the G93A mice and in FALS patients with SOD1 mutations.

63 n order to clarify the role of astrocytes in FALS, we deleted MTSOD1 in astrocytes of G85R transgenic

64 ymes initiate the neuropathologic changes in FALS.

65 rly signs of incipient motor neuron death in FALS.

66 that may contribute to neurodegeneration in FALS.

67 taining protein species produced not only in FALS caused by SOD1 mutation, but also in SALS.

68 re identical to those previously reported in FALS cases.

69 g the common missense mutations resulting in FALS.

70 of SOD mutants may play a causative role in FALS and that aberrant copper chemistry, decreased therm

71 s regarding the relevance of elevated ROS in FALS raised by in vitro experiments.

72 y underlie the aggregation of mutant SOD1 in FALS.

73 ights possible new therapeutic strategies in FALS.

74 ant SOD1s may contribute to SOD1 toxicity in FALS.

75 ghlights the importance of this cell type in FALS.

76 proach to investigate the role of the UPR in FALS.

77 per or zinc binding to a subset of "WT-like" FALS mutants (A4V, L38V, G41S, G72S, D76Y, D90A, G93A, a

78 These results indicate that 21q linked FALS is not a primary disorder of astrocytes, and that e

79 spinal cord SOD1 common to both SOD1-linked FALS and SALS, but not present in normal or disease-affe

80 atients in different kindreds of sod1-linked FALS may result from an as yet unidentified property of

81 suggest a unifying mechanism for SOD1-linked FALS pathogenesis.

82 via an excitotoxic mechanism in SOD1-linked FALS.

83 rse side-chains throughout the protein: many FALS mutations reduce structural integrity, lowering the

84 press SOD1-H46R/H48Q, which combines natural FALS mutations at ligands for copper and which is inacti

85 s (ALS) have familial ALS (FALS), and 20% of FALS are caused by mutations of superoxide dismutase typ

86 the underlying cause of approximately 20% of FALS cases.

87 re familial (FALS), and approximately 25% of FALS cases are caused by mutations in Cu/Zn superoxide d

88 n FUS are causal in approximately 4 to 5% of FALS and some apparent SALS cases.

89 rous advances in recent years, nearly 50% of FALS cases have unknown genetic aetiology.

90 ort free-cysteine-independent aggregation of FALS mutant SOD as an integral part of FALS pathology.

91 tation is both the most commonly detected of FALS-associated SOD1 mutations and among the most clinic

92 linked to a particularly aggressive form of FALS aggregates in vitro, while wild-type SOD1 (WT) is s

93 in FUS account for only a small fraction of FALS and SALS, our data suggest that FUS protein may be

94 We have used a transgenic model of FALS based on expression of mutant human Cu,ZnSOD to exp

95 We have developed a cell culture model of FALS in which a motor neurone cell line (NSC34) has been

96 atients and in the transgenic mouse model of FALS, is not observed in Drosophila.

97 otect MNs in an in vitro and animal model of FALS.

98 of ALS derives in part from rodent models of FALS based upon dominant mutations within the superoxide

99 filaments resemble those seen in neurons of FALS patients and bind both Congo red and thioflavin T,

100 The palmitoylation of FALS-linked mtSOD1s (A4V and G93A) was significantly inc

101 The palmitoylation of FALS-linked mtSOD1s (G93A and G85R) was also increased r

102 on of FALS mutant SOD as an integral part of FALS pathology.

103 ing a role for copper in the pathogenesis of FALS linked to SOD1 mutations.

104 ER stress is involved in the pathogenesis of FALS.

105 c oxide metabolism in the pathophysiology of FALS.

106 imer could slow the onset and progression of FALS.

107 pper chaperone for SOD1 (CCS) in a series of FALS-linked SOD1 mutant mice.

108 The loss of metal ion binding specificity of FALS mutant CuZnSODs in vitro may be related to their ro

109 nal transport in a manner similar to that of FALS-linked mutant SOD1.

110 athway distinct from SALS and other types of FALS.

111 that the UPR has a significant influence on FALS, and suggest that enhancing the UPR may be effectiv

112 lay a role in the toxicity of this and other FALS CuZnSOD mutations.

113 of several of these molecules, A4V and other FALS-linked SOD1 mutants such as G93A and G85R behaved s

114 The postmortem FALS brain is characterized by SOD1 inclusions in the mo

115 Most of the "metal binding region" FALS mutants (H46R, G85R, D124V, D125H, and S134N) exhib

116 with familial amyotrophic lateral sclerosis (FALS) (Ala(4) --> Val, Gly(93) --> Ala, and Leu(38) -->

117 t of familial amyotrophic lateral sclerosis (FALS) and accounts for some 20% of the known familial ca

118 s of familial amyotrophic lateral sclerosis (FALS) are associated with mutations in the gene encoding

119 s of familial amyotrophic lateral sclerosis (FALS) because it misfolds and aggregates.

120 ause familial amyotrophic lateral sclerosis (FALS) by gain of an aberrant function that is not yet we

121 % of familial amyotrophic lateral sclerosis (FALS) cases.

122 b to familial amyotrophic lateral sclerosis (FALS) develop a rapidly progressive and fatal motor neur

123 from familial amyotrophic lateral sclerosis (FALS) exhibit point mutations in the gene encoding Cu-Zn

124 Familial amyotrophic lateral sclerosis (FALS) has been linked in some families to dominant mutat

125 d to familial amyotrophic lateral sclerosis (FALS) have begun to define the role of misfolding and ag

126 ause familial amyotrophic lateral sclerosis (FALS) have heightened reactivity with (-)ONOO and H(2)O(

127 Familial amyotrophic lateral sclerosis (FALS) is a fatal motor neuron disease that is caused by

128 Familial amyotrophic lateral sclerosis (FALS) is caused, in 20% of cases, by mutations in the Cu

129 Familial amyotrophic lateral sclerosis (FALS) is linked to over 90 point mutations in superoxide

130 n in familial amyotrophic lateral sclerosis (FALS) is unknown.

131 with familial amyotrophic lateral sclerosis (FALS) possesses dominantly inherited mutations in the ge

132 s in familial amyotrophic lateral sclerosis (FALS) remain incompletely understood.

133 ated familial amyotrophic lateral sclerosis (FALS) results from a toxic gain-of-function of the enzym

134 % of familial amyotrophic lateral sclerosis (FALS) through some, as yet undefined, toxic gain of func

135 l of familial amyotrophic lateral sclerosis (FALS), a fatal disorder characterized by paralysis.

136 ause familial amyotrophic lateral sclerosis (FALS), a fatal neurodegenerative disorder in heterozygot

137 d to familial amyotrophic lateral sclerosis (FALS), a fatal neurodegenerative disorder.

138 ause familial amyotrophic lateral sclerosis (FALS), a neurodegenerative disease resulting from motor

139 ause familial amyotrophic lateral sclerosis (FALS), a rapidly fatal motor neuron disease.

140 s of familial amyotrophic lateral sclerosis (FALS), yet the mechanism by which these lead to cytotoxi

141 n of familial amyotrophic lateral sclerosis (FALS)-associated mutant Cu/Zn superoxide dismutase-1 (SO

142 e of familial amyotrophic lateral sclerosis (FALS).

143 ease familial amyotrophic lateral sclerosis (FALS).

144 ilial form of amyotrophic lateral sclerosis (FALS).

145 with familial amyotrophic lateral sclerosis (FALS).

146 nked familial amyotrophic lateral sclerosis (FALS).

147 d in familial amyotrophic lateral sclerosis (FALS).

148 m of familial amyotrophic lateral sclerosis (FALS).

149 ease familial amyotrophic lateral sclerosis (FALS).

150 d to familial amyotrophic lateral sclerosis (FALS).

151 s of familial amyotrophic lateral sclerosis (FALS).

152 nant familial amyotrophic lateral sclerosis (FALS).

153 n in familial amyotrophic lateral sclerosis (FALS).

154 ause familial amyotrophic lateral sclerosis (FALS).

155 d in familial amyotrophic lateral sclerosis (FALS).

156 ease familial amyotrophic lateral sclerosis (FALS).

157 d to familial amyotrophic lateral sclerosis (FALS); however, it is not clear how FUS mutations cause

158 sis (familial amyotrophic lateral sclerosis, FALS) associated with the most common copper/zinc supero

159 ore provide a molecular basis for the single FALS disease phenotype resulting from mutations of diver

160 nt was either absent or mild in the A4V SOD1 FALS subjects and severe in the SALS subjects.

161 al a common mechanism whereby different SOD1 FALS mutants may result in neuronal injury and suggest a

162 pathogenic pathway underlying SALS, non-SOD1 FALS, ALS/dementia, and related disorders.

163 ective degeneration of motor neurons in SOD1-FALS.

164 n in neuromuscular junctions, where the SOD1-FALS degenerative process is though to initiate, suggest

165 ascorbic acid as the reductant, suggest that FALS mutations in SOD may influence the efficiency of re

166 The FALS Sod mutations alone caused a recessive phenotype, u

167 We cloned the FALS mutant, G93A, and wild-type cDNA of human Cu,Zn-SOD

168 d survival in transgenic mice expressing the FALS-linked mutation in which glycine is substituted by

169 We cloned the cDNA for the FALS A4V mutant, overexpressed the protein in Sf9 insect

170 the motor neurons were more frequent in the FALS A4V subjects.

171 In the 2 affected individuals in the FALS family, we detected both a mutation in the 5' end o

172 spinal cord motor neuron degeneration in the FALS-transgenic mice.

173 The affected regions of the FALS brain are characterized by aggregated SOD1, and the

174 in contrast to the subunit structures of the FALS G37R mutant of human SOD1 and in bovine Cu,Zn SOD.

175 ic studies showing the active channel of the FALS mutant is slightly larger than that of the wild-typ

176 In cultured cells, all 11 of the FALS variants tested produced insoluble forms of mutant

177 70, Hsp27, or Hsp25) block the uptake of the FALS-associated mutant SOD1 (G37R, G41D, or G93A), while

178 From these studies it was concluded that the FALS mutant CuZnSOD apoproteins, in direct contrast to t

179 ere found to be similar, suggesting that the FALS mutant enzyme is not inactivated at a higher rate t

180 Thus, the FALS symptoms are not associated with the reduction in t

181 the minimal SOD activity associated with the FALS Sod mutations appears to determine longevity, not b

182 cerebral cortex of transgenic mice with the FALS-associated G93A mutation.

183 the effect of WTSOD1 overexpression in this FALS mouse model is mutant-specific.

184 OD1-dependent pathogenic mechanism common to FALS and SALS.

185 Expression of two FALS-related mutant SODs (A4V and V148G) caused death of

186 of at least one mutant SOD1 associated with FALS involves increased protein nitration and oxidative

187 A, two of the mutant enzymes associated with FALS, were shown to catalyze the oxidation of a model su

188 genetic linkage screen in 16 pedigrees with FALS with no evidence for mutations in the SOD1 gene and