ライフサイエンスコーパス: IBMPFD

1 IBMPFD mutants avidly bind to these small inclusions and

2 IBMPFD mutants have single amino-acid substitutions at t

3 IBMPFD-associated mutations disrupt binding of VCP to NF

4 IBMPFD/ALS mutations in VCP disrupt autophagosome and en

5 In addition, IBMPFD mutations in p97/VCP lead to accumulation of auto

6 hagic inhibition, similar to that seen after IBMPFD mutant expression.

7 The structures of p97 N-D1 fragments bearing IBMPFD mutations adopt an atypical N-domain conformation

8 ncrease in ubiquitinated proteins induced by IBMPFD mutations in p97/VCP may ultimately lead to anima

9 sults suggest that VCP disease mutants cause IBMPFD through a gain-of-function mechanism, and that VC

10 Identification of VCP as causing IBMPFD has important implications for other inclusion-bo

11 Walker A and B mutations, to disease-causing IBMPFD mutations, and to the presence of the N domain bi

12 In a subset of cells, IBMPFD mutations also promote formation of aggregates th

13 ing p97/VCP-WT (TgVCP-WT) or the most common IBMPFD mutant, p97/VCP R155H (TgVCP-RH), under a muscle-

14 Paget disease with frontotemporal dementia (IBMPFD) and other neurodegenerative disorders.

15 se of the bone, and frontotemporal dementia (IBMPFD) and they account for 1%-2% of familial amyotroph

16 disease of bone and frontotemporal dementia (IBMPFD) is a dominant progressive disorder that maps to

17 disease of bone and frontotemporal dementia (IBMPFD) is a dominantly inherited degenerative disorder

18 disease of bone and frontotemporal dementia (IBMPFD) is a dominantly inherited degenerative disorder

19 ase of the bone and frontotemporal dementia (IBMPFD) is a multisystem degenerative disorder caused by

20 disease of bone and frontotemporal dementia (IBMPFD).

21 ase of the bone and frontotemporal dementia (IBMPFD).

22 Paget disease, and Frontotemporal Dementia (IBMPFD).

23 Paget disease, and Frontotemporal Dementia (IBMPFD).

24 se of the bone, and frontotemporal dementia (IBMPFD).

25 ase of the bone and frontotemporal dementia (IBMPFD).

26 se of the bone and fronto-temporal dementia (IBMPFD) is a progressive autosomal dominant disorder cau

27 se of the bone and fronto-temporal dementia (IBMPFD).

28 parate North American kindreds accounted for IBMPFD in approximately 50% of affected families.

29 ochondrial fusion and respiratory defects in IBMPFD patient fibroblasts.

30 One pathologic feature in IBMPFD is ubiquitinated inclusions, suggesting that muta

31 replicating the major pathology observed in IBMPFD and other TDP-43 proteinopathies.

32 ne protein such as expanded polyglutamine in IBMPFD mutant cells results in an increase in aggregated

33 red autophagy explains the pathology seen in IBMPFD muscle, including TDP-43 accumulation.

34 Because 90% of IBMPFD patients have myopathy, we generated an in vivo I

35 The pathological mechanism of IBMPFD is not clear and there is no treatment.

36 The mechanism of IBMPFD pathogenesis is unknown.

37 oped and characterized a Drosophila model of IBMPFD (mutant-VCP-related degeneration).

38 t this may contribute to the pathogenesis of IBMPFD.

39 Our data broaden the phenotype of IBMPFD to include motor neuron degeneration, suggest tha

40 w that p97/VCP containing the most prevalent IBMPFD-associated mutation, R155H, has normal ATPase act

41 C6 improves aggresome formation and protects IBMPFD mutant cells from polyglutamine-induced cell deat

42 dementia and amyotrophic lateral sclerosis (IBMPFD/ALS).

43 ed in cultured cells, both this and a second IBMPFD-associated p97/VCP mutant increase the overall le

44 Similarly, IBMPFD mutant VCP expression in cells and animals leads

45 We conclude that IBMPFD mutations in p97/VCP disrupt ERAD and that this m

46 In this study, we find that IBMPFD muscle also accumulates autophagosome-associated

47 We propose that IBMPFD mutations alter the timing of the transition betw

48 The present study shows that IBMPFD mutant expression increases ubiquitinated protein

49 se deficient p97/VCP mutant and suggest that IBMPFD mutations impair p97/VCP cellular function.

50 may disrupt mTOR signaling and contribute to IBMPFD/ALS disease pathogenesis.

51 a disruption in this process contributes to IBMPFD pathogenesis.

52 ients have myopathy, we generated an in vivo IBMPFD model in adult Drosophila muscle, which recapitul

53 tissue damage and cell death associated with IBMPFD models in Drosophila.

54 We investigated 13 families with IBMPFD linked to chromosome 9 using a candidate-gene app

55 ating the spectrum of disease in humans with IBMPFD.

56 nd cognitive delay observed in patients with IBMPFD and neurofibromatosis type 1.

57 One-third of patients with IBMPFD develop frontotemporal dementia, characterized by