ライフサイエンスコーパス: ataxin-2

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

47 -43, FUS (fused in sarcoma), angiogenin, and ataxin-2 in amyotrophic lateral sclerosis; ataxin-2 in s

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

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

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

51 Ataxin 2 intermediate-length polyglutamine (polyQ) expan

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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