ライフサイエンスコーパス: ataxin-2

1 omotes the ubiquitylation and degradation of Ataxin-2.

2 ues, similar to the expression of endogenous ataxin-2.

3 h caused by expression of full-length mutant ataxin-2.

4 tic strategy for ALS that involves targeting ataxin-2.

5 enrichment of A2BP1 in the same fractions as ataxin-2.

6 protein 1) which binds to the C-terminus of ataxin-2.

7 e-length polyglutamine (polyQ) expansions of Ataxin-2, a like-Sm (LSm) RBP, are associated with incre

8 e TDP-43 pathology when programmed to target ataxin-2, a modifier of TDP-43-associated toxicity.

9 sed by expansion of a polyglutamine tract in ataxin-2, a protein of unknown function.

10 ytoskeletal structure resulting from altered ataxin-2 activity is responsible for neurodegeneration i

11 No overlap in ataxin-2 allele size between normal and disease chromoso

12 o these granules promotes the degradation of Ataxin-2, allowing for the translation of Xbp1 mRNA and

13 Yeast ataxin-2, also known as Pbp1 (polyA binding protein-bind

14 Yeast ataxin-2, also known as Pbp1, senses the activity state

15 ng the rules that govern the condensation of ataxin-2, an SG protein implicated in neurodegenerative

16 ed antibodies to three antigenic peptides of ataxin-2 and analyzed the expression pattern of ataxin-2

17 ls increased cell death compared with normal ataxin-2 and elevated the levels of activated caspase-3

18 hmark RNA-targeting CRISPR platforms against ataxin-2 and find that high-fidelity forms of Cas13 poss

19 Here, we demonstrate that ataxin-2 and its Drosophila homolog, ATX2, assemble with

20 ing the binding of 2 of its client proteins, ataxin-2 and Sf3b2.

21 oteins implicated in neurodegeneration (i.e. Ataxin-2 and SMN) interact with stress granules.

22 The normal cellular function of ataxin-2 and the mechanism by which polyglutamine expans

23 The normal cellular function of ataxin-2 and the mechanism by which polyglutamine expans

24 a link between cell death mediated by mutant ataxin-2 and the stability of the Golgi complex.

25 isposing to ALS and that polyQ expansions in ataxin 2 are a significant risk factor for the disease.

26 lyglutamine (polyQ) expansions (27-33 Qs) in ataxin 2 as a genetic risk factor for sporadic ALS in No

27 We identify the RNA binding protein Ataxin-2 as a substrate of Fbxo42, which, as part of a S

28 We found that the C. elegans ortholog of ataxin 2, ATX-2, forms a complex with PAB-1, a cytoplasm

29 gile X mental retardation protein (FMRP) and Ataxin-2 (Atx2) are triplet expansion disease- and stres

30 Ataxin-2 (Atx2) is a translational control molecule muta

31 We found that ATAXIN-2 (ATX2), an RNA-associated protein involved in n

32 We found that the Drosophila homolog of ATAXIN-2 (ATX2)--an RNA-binding protein implicated in hu

33 lutamine) expansion in the cytosolic protein ataxin-2 (Atx2).

34 olyglutamine tracts in the cytosolic protein ataxin-2 (Atx2).

35 Here we show that ataxin 2 (ATXN2), a polyglutamine (polyQ) protein mutate

36 ermediate CAG (polyQ) expansions in the gene ataxin-2 (ATXN2) are now recognized as a risk factor for

37 Intermediate-length repeat expansions in ATAXIN-2 (ATXN2) are the strongest genetic risk factor f

38 Ataxin-2 (ATXN2) homologs exist in all eukaryotic organi

39 Expanded glutamine repeats of the ataxin-2 (ATXN2) protein cause spinocerebellar ataxia ty

40 SGs), and lowering the SG-associated protein ataxin-2 (ATXN2) using Atxn2-targeting antisense oligonu

41 Ataxin-2 (ATXN2), an RNA-binding protein harboring 22-po

42 h antineoplastic assay and identified A2BP1 (ataxin 2 binding protein 1, Rbfox1), an RNA-binding and

43 there are at least two Fox-1-related genes, ataxin-2 binding protein 1 (A2BP1)/Fox-1 and Fxh/Rbm9, w

44 ndians (n = 413) identified variation in the ataxin-2 binding protein 1 gene (A2BP1) that was associa

45 ystem, we identified a novel protein, A2BP1 (ataxin-2 binding protein 1) which binds to the C-terminu

46 we report functional analysis of Drosophila Ataxin 2-binding protein 1 (A2BP1) during this process.

47 pends on the Drosophila homolog of the human ataxin 2-binding protein 1 (A2BP1) gene.

48 We show that Fox-1/Ataxin 2-Binding Protein 1 (A2BP1), a protein implicated

49 Here, we report that regulation of Ataxin-2 by Fbxo42 is a crucial step during UPR-induced

50 ibility that polyglutamine expansions within ataxin-2 cause neurodegeneration by interfering with the

51 echanism by which polyglutamine expansion of ataxin-2 causes neurodegeneration are unknown.

52 echanism by which polyglutamine expansion of ataxin-2 causes neurodegeneration remain unknown.

53 of cis and trans interactions that fine-tune ataxin-2 condensation and reveal an unexpected molecular

54 ponent of nearly all cases of ALS, targeting ataxin-2 could represent a broadly effective therapeutic

55 Like human ataxin-2, Datx2 is found throughout development in a var

56 ty in the retina and nervous system, whereas ataxin-2 encoded by a CAA-interrupted repeat or CAA-only

57 We found that ataxin-2 encoded by a pure CAG repeat conferred toxicity

58 These data indicate that ataxin-2 encoded by a pure CAG versus interrupted CAA/G

59 n-2 protein aggregated in the fly eye, while ataxin-2 encoded by either a CAA/G or CAA repeat remaine

60 These findings, coupled with work on other ataxin-2 family members, suggest that ATX2 plays a direc

61 Repeats of CAG in the ataxin 2 gene (ATXN2) in the long-normal range (sometime

62 (CAG) expansion in the coding region of the ataxin 2 gene on chromosome 12q.89 families with autosom

63 This contig contains the Ataxin 2 gene, and it covers the interval harboring the

64 caused by a CAG repeat expansion within the ataxin-2 gene has allowed us to determine the frequency

65 diate-length polyglutamine expansions in the ataxin-2 gene increase risk of ALS.

66 CAG repeat expansions in the ATXN2 (ataxin-2) gene can cause the autosomal dominant disorder

67 sion of a polyglutamine tract in the protein ataxin-2 give rise to the neurodegenerative disorders sp

68 We provide evidence that Ataxin-2 governs motility and translation of neuronal RN

69 RNA of Xbp1 is sequestered and stabilized in Ataxin-2 granules, where it remains untranslated.

70 -43, FUS (fused in sarcoma), angiogenin, and ataxin-2 in amyotrophic lateral sclerosis; ataxin-2 in s

71 xin-2 and analyzed the expression pattern of ataxin-2 in normal and SCA2 adult brains and cerebellum

72 d ataxin-2 in amyotrophic lateral sclerosis; ataxin-2 in spinocerebellar ataxia; and SMN (survival of

73 labeling of Purkinje cells; (3) the level of ataxin-2 increased with age in Purkinje cells of normal

74 Ataxin 2 intermediate-length polyglutamine (polyQ) expan

75 results provide mechanistic insight into how ataxin 2 intermediate-length polyQ expansions could cont

76 Human ataxin 2 is a protein of unknown function that is implic

77 BP1, are a known ALS genetic risk factor and ataxin 2 is a stress granule component in mammalian cell

78 However, the wild-type function of ataxin-2 is yet to be determined.

79 The SCA2 gene product, ataxin-2, is a basic protein with two domains (Sm1 and S

80 ns associated with ALS, including TDP-43 and ataxin-2, is that they localize to stress granules.

81 First, we crossed ataxin-2 knockout mice with TDP-43 (also known as TARDBP

82 this association and the obese phenotype of ataxin-2 knockout mice, A2BP1 was genetically and functi

83 eurons in a pattern similar to that seen for ataxin-2 labeling.

84 endent approaches to test whether decreasing ataxin-2 levels could mitigate disease in a mouse model

85 hatase 1 regulatory subunit 36 (PPP1R36) and ataxin 2 like (ATXN2L) in three new biological replicate

86 conducted a proteomics screen and identified ataxin-2-like (ATXN2L) as a muNS-interacting protein.

87 urkinje cells of normal individuals; and (4) ataxin-2-like immunoreactivity in SCA2 brain tissues was

88 e 5' cap in competition with eIF4G1 and that ataxin-2-like promotes FMRP binding to the transcribed b

89 -immunoprecipitation of eIF4E, mRNA targets, ataxin-2-like, and PABPC1.

90 movement of sperm contents and that maternal ataxin-2 maintains paternal DNA and paternal mitochondri

91 the levels of two client proteins (SF3B2 and ataxin-2) of a chaperone protein, heat shock protein 90

92 Our findings support the hypothesis that ataxin 2 plays an important role in predisposing to ALS

93 Because longer ataxin 2 polyQ expansions are associated with a differen

94 Here, we show that intermediate-length ataxin 2 polyQ expansions enhance stress-induced TDP-43

95 We also connect intermediate-length ataxin 2 polyQ expansions to the stress-dependent activa

96 triking association with ALS cases harboring ataxin 2 polyQ expansions.

97 ical feature of ALS with intermediate-length ataxin 2 polyQ expansions.

98 Thus, intermediate-length ataxin 2 polyQ repeat expansions are associated with inc

99 To extend these findings, we assessed the ataxin 2 polyQ repeat length in 1294 European ALS patien

100 We report that Ataxin-2 polyQ expansions aberrantly sequester TDP-43 wi

101 verall, our results support a model in which Ataxin-2 polyQ expansions disrupt stability, localizatio

102 slation of neuronal RNP condensates and that Ataxin-2 polyQ expansions fundamentally perturb spatial

103 Furthermore, the CAG-encoded ataxin-2 protein aggregated in the fly eye, while ataxin

104 at in ATXN2 could impact the toxicity of the ataxin-2 protein in vivo in Drosophila.

105 The toxicity of the CAG-encoded ataxin-2 protein was also sensitive to the translation f

106 observed in ataxin-1[Q80] transgenic lines, ataxin-2[Q58] remained cytoplasmic without detectable ub

107 The decrease in ataxin-2 reduced aggregation of TDP-43, markedly increas

108 letion of ER-exit and trans-Golgi signals in ataxin-2 resulted in an altered subcellular distribution

109 atanin or double depletion of kinesin-13 and ataxin-2 resulted in the capture of the sperm contents b

110 and mRNA regulatory functions of TDP-43 and Ataxin-2 ribonucleoprotein (RNP) condensates in rodent (

111 A decrease in ataxin-2 suppresses TDP-43 toxicity in yeast and flies,

112 In animal models with expression of mutant ataxin-2 targeted to Purkinje cells, neuronal dysfunctio

113 les, we find that the in vivo delivery of an ataxin-2-targeting Cas13 system to a mouse model of TDP-

114 pansion of a polyglutamine (polyQ) repeat in ataxin-2, the SCA2 gene product.

115 CAG repeat encoding a polyglutamine tract in ataxin-2, the SCA2 gene product.

116 ble approach, we administered ASOs targeting ataxin-2 to the central nervous system of TDP-43 transge

117 finity-purified antibodies demonstrated that ataxin 2 was expressed in the cytoplasm of Purkinje cell

118 ataxin-2 were synthesized; (2) the wild-type ataxin-2 was localized in the cytoplasm in specific neur

119 We confirmed that the SCA2 gene product, ataxin-2, was predominantly located in the Golgi apparat

120 To help clarify the function of ataxin-2, we produced antibodies to three antigenic pept

121 By immunocfluorescent staining, A2BP1 and ataxin-2 were both localized to the trans -Golgi network

122 that (1) both wild-type and mutant forms of ataxin-2 were synthesized; (2) the wild-type ataxin-2 wa

123 d by the conserved RNA-binding protein ATX-2/Ataxin-2, which targets and maintains ZEN-4 at the spind

124 Expression of full-length ataxin-2 with an expanded repeat disrupted the normal mo

125 Expression of ataxin-2 with expanded repeats in PC12 and COS1 cells in

126 Mice expressing ataxin-2 with Q58 showed progressive functional deficits