ライフサイエンスコーパス: FTDP-17

1 mentia with Parkinsonism-chromosome 17 type (FTDP-17).

2 D) and parkinsonism linked to chromosome 17 (FTDP-17).

3 ia and parkinsonism linked to chromosome 17 (FTDP-17).

4 ia and Parkinsonism linked to chromosome 17 (FTDP-17).

5 a with Parkinsonism linked to chromosome 17 (FTDP-17).

6 D with Parkinsonism linked to chromosome 17 (FTDP-17).

7 ia and parkinsonism linked to chromosome 17 (FTDP-17).

8 entia with parkinsonism--chromosome 17 type (FTDP-17).

9 ith parkinsonism linked to chromosome 17q21 (FTDP-17).

10 etically linked to frontotemporal dementias (FTDP-17).

11 a with parkinsonism linked to chromosome 17 (FTDP-17).

12 a with parkinsonism linked to chromosome 17 (FTDP-17).

13 a with parkinsonism linked to chromosome 17 (FTDP-17).

14 D with parkinsonism linked to chromosome 17 (FTDP-17).

15 ia and parkinsonism linked to chromosome 17 (FTDP-17).

16 Parkinsonism associated with chromosome 17 (FTDP-17).

17 initiate the formation of tau inclusions in FTDP-17.

18 au the filament formation that characterizes FTDP-17.

19 molecular causes of the inherited tauopathy, FTDP-17.

20 pathology described in several families with FTDP-17.

21 well as in cases of Alzheimer's disease and FTDP-17.

22 abnormal ratios of tau isoforms, leading to FTDP-17.

23 ing a possible mechanism for parkinsonism in FTDP-17.

24 ght lead to a novel therapeutic strategy for FTDP-17.

25 s with Parkinsonism linked to chromosome 17 (FTDP-17), a major class of inherited dementing disorders

26 entia with parkinsonism, chromosome 17 type (FTDP-17), a recently defined disease entity, is clinical

27 at many of the sites hyperphosphorylated in FTDP-17, AD, and other tauopathies.

28 he N-terminus of tau, found in patients with FTDP-17, affect its binding to dynactin, which is abnorm

29 In FTDP-17, Alzheimer's disease, and other tauopathies, agg

30 We found that the FTDP-17 amino acid substitutions G272V (in both 3-repeat

31 ia and Parkinsonism linked to chromosome 17 (FTDP-17), an autosomal dominant condition leading to neu

32 a with Parkinsonism linked to chromosome 17 (FTDP-17), an autosomal dominant neurodegenerative disord

33 to aberrant splicing have been identified in FTDP-17, an autosomal dominant hereditary neurodegenerat

34 quired age-dependent CNS pathology similarto FTDP-17 and ALS/PDC, including insoluble, hyperphosphory

35 ltiple tau gene mutations are pathogenic for FTDP-17 and tau polymorphisms appear to be genetic risk

36 cations for future drug trial development in FTDP-17 and the sporadic tauopathies.

37 ia and Parkinsonism linked to chromosome 17 (FTDP-17) and Alzheimer's disease (AD).

38 a with parkinsonism linked to chromosome 17 (FTDP-17) and Alzheimer's disease.

39 a with parkinsonism linked to chromosome 17 (FTDP-17) and amyotrophic lateral sclerosis/parkinsonism-

40 a with parkinsonism linked to chromosome 17 (FTDP-17), and common variation in MAPT is strongly assoc

41 ia and parkinsonism linked to chromosome 17 (FTDP-17), and tau aggregates are present in Alzheimer's

42 Genetic tau mutations can cause FTDP-17, and mice overexpressing tau mutants such as P30

43 n the tau gene, and the signature lesions of FTDP-17 are filamentous tau inclusions.

44 a with parkinsonism linked to chromosome 17 (FTDP-17), are caused by mutations in the same gene.

45 ain the phenotypic heterogeneity observed in FTDP-17, as exemplified by an unusual family described h

46 FTDP-17 begins with executive function deficits and othe

47 dreds are diverse, the diagnostic lesions of FTDP-17 brains are tau-rich filaments in the cytoplasm o

48 t co-migrated with insoluble tau from AD and FTDP-17 brains.

49 ersed filaments from Alzheimer's disease and FTDP-17 brains.

50 ) with parkinsonism linked to chromosome 17 (FTDP-17), but those in exon 10 (E10) or the following in

51 cognitive function in mouse models of AD and FTDP-17, but the mechanisms regulating the turnover of p

52 Thus, tau mutations cause FTDP-17 by multiple pathological mechanisms, which may e

53 hus, this novel Glu342Val mutation may cause FTDP-17 by unprecedented mechanisms that alter splicing

54 Excess E10 inclusion in FTDP-17 can be caused by intronic mutations destabilizin

55 urprising that the pathology associated with FTDP-17 can vary widely as well.

56 e coding region of five genes, mapped to the FTDP-17 candidate region, were also sequenced.

57 All AGD, TPSD, FAD, and FTDP-17 cases had significant AC-K280 reactivity that wa

58 Most FTDP-17 cases show neuronal and/or glial inclusions that

59 Although R406W tau is hyperphosphorylated in FTDP-17 cases, R406W tau expressed in cell model systems

60 nce indicate that the Val279Met change is an FTDP-17 causative mutation.

61 a with Parkinsonism linked to chromosome 17 (FTDP-17), characterized by neuronal pathological Tau inc

62 ia and parkinsonism linked to chromosome-17 (FTDP-17), directly implicate tau abnormalities in the on

63 these results also have implications for the FTDP-17 diseases caused by increased expression of 4R-ta

64 minal tau mutation found in a single case of FTDP-17, enhances the polymerization of the tau molecule

65 We have now sequenced tau in FTDP-17 families and identified three missense mutations

66 coding regions in affected subjects from two FTDP-17 families revealed nine DNA sequence variants, ei

67 ed in exon 10 has been identified in several FTDP-17 families that present with increased exon 10 inc

68 he tau gene have been identified in about 20 FTDP-17 families.

69 A ninth variant (Val279Met) was found in one FTDP-17 family but not in the second FTDP-17 family.

70 in one FTDP-17 family but not in the second FTDP-17 family.

71 ice site of exon 10 in patients from another FTDP-17 family.

72 ia and Parkinsonism linked to chromosome 17 (FTDP-17) form filamentous structures.

73 roup of neurodegenerative dementias known as FTDP-17 (fronto-temporal dementia with Parkinsonism link

74 ction of neurodegenerative diseases known as FTDP-17 (fronto-temporal dementias and Parkinsonism link

75 e from patients with Alzheimer's disease and FTDP-17 (frontotemporal dementia and parkinsonism linked

76 n cause neurodegeneration and imply that the FTDP-17 gene is the tau gene.

77 he discovery of mutations in the tau gene in FTDP-17 has firmly established the relevance of tau path

78 ia and parkinsonism linked to chromosome 17 (FTDP-17), historically termed Pick's disease.

79 imal downstream intron of tau exon 10 at the FTDP-17 hotspot region; and that hnRNPG and hnRNPE2 inte

80 a with parkinsonism linked to chromosome 17 (FTDP-17), implying that tau abnormalities by themselves

81 g mice, respectively) that is pathogenic for FTDP-17 in several kindreds.

82 ntotemporal dementia and a family history of FTDP-17 in whom we found a novel E12 (Glu342Val) tau gen

83 a with parkinsonism linked to chromosome 17 (FTDP-17), in order to study the neuroprotective capacity

84 ia and parkinsonism linked to chromosome 17 (FTDP-17), in which both RNA splicing and amino acid subs

85 t it is probably outside the D17S800-D17S791 FTDP-17 interval.

86 One of the major disease mechanisms in FTDP-17 is the increased inclusion of tau exon 10 during

87 a with Parkinsonism linked to chromosome 17 (FTDP-17) is a group of related disorders frequently char

88 ia and Parkinsonism linked to chromosome 17 (FTDP-17) is an autosomal dominant neurodegenerative diso

89 mentia with parkinsonism chromosome 17 type (FTDP-17) is caused by mutations in MAPT, the gene encodi

90 a with parkinsonism linked to chromosome 17 (FTDP-17) is caused by mutations in the MAPT gene, encodi

91 entia with parkinsonism, chromosome 17 type (FTDP-17) is caused by mutations in the tau gene, and the

92 s in the neuronal loss observed in different FTDP-17 kindreds are diverse, the diagnostic lesions of

93 e PPND kindred and Pro301(Leu) in four other FTDP-17 kindreds, were found.

94 ing observed in both frontal variant FTD and FTDP-17 linked to the tau(V337M) mutation in humans.

95 Previous studies have mapped the FTDP-17 locus to a 2-centimorgan region on chromosome 17

96 ally expressed recombinant tau proteins with FTDP-17 missense mutations cause functional impairments,

97 s of recombinant tau proteins with different FTDP-17 missense mutations implicated all but one of the

98 vivo We express wild-type human tau and five FTDP-17 mutant forms of tau in Drosophila using a site-d

99 Both wild-type and FTDP-17 mutant GFAP/tau Tg animals manifest an age-depen

100 We expressed normal and FTDP-17 mutant human tau (mutations P301L and V337M) in

101 agenesis using as backbones the wild type or FTDP-17 mutant R406W Tau.

102 model for tauopathies using human normal and FTDP-17 mutant tau as transgenes.

103 hanism of neurotoxicity of wild-type tau and FTDP-17 mutant tau in disease pathogenesis.SIGNIFICANCE

104 In vitro, FTDP-17 mutant versions of tau can reduce microtubule bi

105 ompared wild type four-repeat tau with three FTDP-17 mutants (P301L, V337M and R406W) for their abili

106 the toxicity of wild-type tau and of all the FTDP-17 mutants tested.

107 e function of which is abolished by a silent FTDP-17 mutation (L284(L)), resulting in excess E10 incl

108 sion of human tau containing the most common FTDP-17 mutation (P301L) results in motor and behavioura

109 FTDP-17 mutation lines had a more severe Unc phenotype,

110 ng the human tau(V337M) ('Seattle Family A') FTDP-17 mutation, which we have previously shown to demo

111 We find that FTDP-17 mutations act to enhance phosphorylation of tau

112 Several FTDP-17 mutations affect alternative splicing and result

113 However, FTDP-17 mutations affect the strength of cis-splicing el

114 sm of normal E10 splicing regulation and how FTDP-17 mutations alter splicing, mutational analysis of

115 RNA-splicing FTDP-17 mutations alter the wild-type approximately 50:5

116 press tau harboring one or several different FTDP-17 mutations and showed that different tau mutants

117 isms of disease progression may differ among FTDP-17 mutations and that the effects of the varying mu

118 We generated recombinant forms of 12 FTDP-17 mutations chosen for their predicted effects on

119 FTDP-17 mutations in the tau gene lead to early onset fr

120 nking the 5' splice site of E10 and intronic FTDP-17 mutations in this element enhance E10 inclusion.

121 gth of the cis-splicing elements affected by FTDP-17 mutations.

122 correct aberrant E10 splicing resulting from FTDP-17 mutations.

123 by phosphorylation-mimicking mutations or by FTDP-17 mutations.

124 a with parkinsonism linked to chromosome-17 (FTDP-17; n = 2; MAPT p.P301L and IVS10 + 16).

125 Genetic mutations associated with FTDP-17 often affect tau exon 10 alternative splicing.

126 ypical cognitive and behavioural features of FTDP-17, one patient is exhibiting an atypical neuropsyc

127 ernative splicing defects of tau as found in FTDP-17 patients can be corrected by application of anti

128 le and insoluble tau proteins from brains of FTDP-17 patients indicated that different pathogenic mut

129 Importantly, the FTDP-17 phenotype is transmitted in a dominant rather th

130 hysical properties that promote onset of the FTDP-17 phenotype, including neuronal cell death by eith

131 In contrast, the FTDP-17 R406W mutation (which maps in a regulatory regio

132 e whether the formation of tau inclusions in FTDP-17 results from an alteration in the ability of mut

133 Thus far, tau FTDP-17 splicing mutations affect six predicted cis-regu

134 se mutations cause diverse neurodegenerative FTDP-17 syndromes by multiple mechanisms.

135 stigated the possibility that PPND and other FTDP-17 syndromes might be caused by mutations in the ta

136 rs of the same kindred often exhibit diverse FTDP-17 syndromes, which suggests that additional geneti

137 Since FTDP-17 tau gene mutations alter levels/functions of tau

138 o investigate the biological consequences of FTDP-17 tau mutants and assess their ability to form fil

139 tes, result from the expression of different FTDP-17 tau mutants in transfected Chinese hamster ovary

140 flies expressing wild-type human and various FTDP-17 tau mutants, supporting a conserved mechanism of

141 Here, we show that four of the FTDP-17 tau mutations, R406W, V337M, G272V, and P301L, r

142 Furthermore, by combining two FTDP-17 Tau variants (either P301L or P301S with S320F),

143 re model, we examined a multitude of genetic FTDP-17 Tau variants for their ability to be seeded by e

144 findings revealed stark differences between FTDP-17 Tau variants in their ability to be seeded, with

145 mechanistic differences between wildtype and FTDP-17 Tau variants, as well as different Tau isoforms,

146 o the neuronal cell loss that occurs in this FTDP-17 tauopathy.

147 , frontotemporal dementia with Parkinsonism (FTDP-17), the early onset dementia observed in Down synd

148 ia and parkinsonism linked to chromosome 17 (FTDP-17), thereby proving that tau dysfunction can direc

149 ia and parkinsonism linked to chromosome 17 (FTDP-17) through comprehensive neurobehavioural examinat

150 a with parkinsonism linked to chromosome 17 (FTDP-17) unequivocally confirmed the central role of tau

151 elate with disease-related factors in AD and FTDP-17, we have performed real-time surface plasmon res

152 uronal and glial inclusions of patients with FTDP-17 were robustly AC-K280 reactive.

153 a with parkinsonism linked to chromosome 17 (FTDP-17), which has clinical and molecular similarities

154 ia and parkinsonism linked to chromosome 17 (FTDP-17), which is caused by mutations in tau.

155 ognitive and behavioural features typical of FTDP-17, which have proved challenging to manage despite

156 present in the frontal cortex from a case of FTDP-17 with the P301L tau mutation.

157 ia and parkinsonism linked to chromosome 17 (FTDP-17), with filamentous tau aggregates as the major l