ライフサイエンスコーパス: progerin

1 ases transcripts for a truncated prelamin A (progerin).

2 /+ mice (which produce lamin A, lamin C, and progerin).

3 rboxymethylation of the mutant LA (LADelta50/progerin).

4 a truncated farnesylated-prelamin A protein (progerin).

5 nally truncated form of farnesyl-prelamin A (progerin).

6 sulting in a mutant lamin A protein known as progerin.

7 so known as PRKDC) as a downstream target of progerin.

8 GPS fibroblasts, increasing the synthesis of progerin.

9 ogeria caused by the expression of LADelta50/progerin.

10 tion of a mutant form of prelamin A known as progerin.

11 of a truncated, prenylated prelamin A called progerin.

12 orm of prelamin A, which is generally called progerin.

13 foci in the primary keratinocytes expressing progerin.

14 roduction of a mutant lamin A protein termed progerin.

15 1) is impaired in cells expressing LADelta50/progerin.

16 as in HGPS cells and in cells expressing GFP-progerin.

17 and/or carboxylmethyl CaaX modifications on progerin.

18 n contrast, this cleavage site is deleted in progerin.

19 isorder caused by the mutant lamin-A protein progerin.

20 ulting in the production of a protein called progerin.

21 ing disease caused by a toxic protein called progerin.

22 the forks, whereas PCNA efficiently bound to progerin.

23 of a toxic form of lamin A, which is termed progerin.

24 ults indicated that STXBP5 bound directly to progerin.

25 ated CVD and aging induced by prelamin A and progerin.

26 tic disorder caused by the prelamin A mutant progerin.

27 trapping of NRF2 at the nuclear periphery by progerin.

28 A yielding the farnesylated aberrant protein progerin.

29 ng function of LAP2alpha in cells expressing progerin.

30 ulting in a truncated form of lamin A called progerin.

31 ected from functional deleterious effects of progerin.

32 ing the production of a toxic isoform called progerin.

33 ng toxicity of the disease-producing protein progerin.

34 is sufficient to induce ROS irrespective of progerin.

35 ng disorder caused by a lamin A mutant named progerin.

36 ssion of a truncated form of Lamin A, called progerin.

37 dominant-negative lamin A protein, known as progerin.

38 s the farnesylated aberrant lamin A protein, progerin.

39 Also, in knockin mice expressing exclusively progerin (a toxic form of prelamin A found in Hutchinson

40 ease is caused by constitutive production of progerin, a mutant form of the nuclear architectural pro

41 ascular pathologies due to the expression of progerin, a mutant form of the nuclear envelope protein

42 s a rare disease caused by the expression of progerin, a mutant protein that accelerates aging and pr

43 Progerin, a mutated lamin A, causes the severe premature

44 Progerin, a product of LMNA mutation, leads to multiple

45 tation causes RNA mis-splicing that produces progerin, a toxic protein that induces rapid ageing and

46 Our approach involves expression of progerin, a truncated form of lamin A associated with pr

47 (LMNA) gene, resulting in the generation of progerin, a truncated splicing mutant of lamin A.

48 The disease is provoked by progerin, a variant of lamin A expressed in most differe

49 we present evidence that the mutant lamin A (progerin) accumulates in the nucleus in a cellular age-d

50 Progerin accumulation has not only been described in HGP

51 Progerin accumulation is associated with impaired turnov

52 Importantly, progerin accumulation stimulates a powerful suppression

53 tures, we observed, concomitantly to nuclear progerin accumulation, severe nuclear envelope deformati

54 The expression of progerin acted in a dominant-negative fashion to disrupt

55 localization by the disease-causing protein, progerin, activates mTORC1 and inhibits autophagy, pheno

56 Hutchinson-Gilford progeria syndrome (termed progerin) acts as a dominant negative protein that chang

57 The presence of progerin adversely affects the integrity of the nuclear

58 Progerin affected both the coupling of the nucleus to ac

59 However, very little is known about how progerin affects SMC contractility.

60 A progerin allele of lamin-A is regulated in the same mann

61 Because progerin also accumulates during physiological ageing, o

62 Progerin also accumulates during physiological aging.

63 ading us to hypothesize that nonfarnesylated progerin also might be capable of eliciting disease.

64 In HGPS a mutation in lamin A (progerin) alters nuclear morphology and gene expression.

65 ely rare disease caused by the expression of progerin, an aberrant protein produced by a point mutati

66 g disorder caused by nuclear accumulation of progerin, an altered form of the Lamin A gene.

67 ation of RNA mis-splicing, reduced levels of progerin and correction of nuclear abnormalities.

68 Our findings indicate that progerin and full-length farnesyl-prelamin A are toxic t

69 e nuclear morphology of cells expressing GFP-progerin and in HGPS cells.

70 Upon differentiation of HGPS-iPSCs, progerin and its ageing-associated phenotypic consequenc

71 Despite the broad expression pattern of progerin and its deleterious effects in many organs, res

72 henotypes of Lmna HG/LCO mice (which produce progerin and lamin C) with littermate Lmna HG/+ mice (wh

73 c lines to assess the effects of suppressing progerin and restoring lamin A ubiquitously at different

74 The relationship between progerin and survival was assessed by using joint modeli

75 an influence both the steady-state levels of progerin and the severity of progeria-like disease pheno

76 ng of the C-terminus of the mutant protein, 'progerin', and found that it does not undergo cleavage a

77 yields an altered form of the protein, named progerin, and an aberrant nuclear shape.

78 HGPS-iPSCs show absence of progerin, and more importantly, lack the nuclear envelop

79 Abnormal lamin A (progerin) appears to accumulate with aging in normal cel

80 ur data suggest that the cellular effects of progerin are transduced, at least in part, through reduc

81 This study aimed to develop a plasma progerin assay to evaluate progerin's quantity, response

82 NRF2 activity in HGPS patient cells reverses progerin-associated nuclear aging defects and restores i

83 esyltransferase inhibitors (FTI) mislocalize progerin away from the nuclear envelope and reduce the f

84 e farnesyltransferase inhibitor mislocalized progerin away from the nuclear envelope to the nucleopla

85 her hypothesized that the mislocalization of progerin away from the nuclear envelope would improve th

86 In this study, we determined that progerin binds directly to lamin A/C and induces profoun

87 h HGPS and in NIH 3T3 fibroblasts expressing progerin, but were restored by inhibiting protein farnes

88 Here we show that reduction of lamin A/progerin by a single-dose systemic administration of ade

89 s pre-lamin A cleavage mimics the effects of progerin by disrupting the Ran gradient, but the effects

90 However, the mechanism how progerin causes disease remains unclear.

91 Progerin causes extensive atherosclerosis and cardiac el

92 We suspected that the expression of progerin changes the overall structure of the nuclear la

93 iduals, but it is not clear if low levels of progerin contribute to the aging of the brain.

94 al was associated with both the magnitude of progerin decrease and duration at lower levels.

95 b treatment resulted in an average per-visit progerin decrease from baseline of between 35% to 62% (a

96 The magnitude of progerin decrease positively associated with patient sur

97 Analyses including NLS swapping revealed Progerin did not cause global inhibition of nuclear impo

98 However, the impact of progerin-driven VSMC defects on endothelial cells (ECs)

99 Depletion of XPA or progerin each significantly restored PCNA at replication

100 uggest that this approach may be limited, as progerin elicits disease phenotypes whether or not it is

101 ely satisfying because it is unclear whether progerin-even if were expressed in neurons-would be capa

102 Forcing the nuclear localization of Ubc9 in progerin-expressing cells rescues the Ran gradient and T

103 interleukin 17 (IL17) signalling pathway in progerin-expressing cells.

104 Similarly, spontaneous immortalization of progerin-expressing cultured keratinocytes selected for

105 embryo fibroblasts (Lmna-/- MEFs) and human progerin-expressing HGPS fibroblasts both display reduce

106 RNA sequencing to characterize the aorta in progerin-expressing LmnaG609G/G609G mice and wild-type c

107 This defect in progerin-expressing vascular smooth muscle cells is asso

108 at may be mediated in part by a reduction in progerin expression and an increase in sirtuin 1 (SIRT1)

109 VB) and found that UVA, but not UVB, induces progerin expression and HGPS-like abnormal nuclear shape

110 Thus, progerin expression disrupts the overall structure of th

111 h ubiquitous, VSMC-, EC- or myeloid-specific progerin expression fed a normal or high-fat diet were u

112 Progerin expression has a dramatic effect on arterial sm

113 ced lamin A expression in wild-type mice and progerin expression in an HGPS mouse model.

114 Both ubiquitous and VSMC-specific progerin expression in Apoe-null mice provoked alteratio

115 ety of cell-based assays, we determined that progerin expression in Hutchinson-Gilford progeria syndr

116 ia syndrome in HeLa cells in which increased progerin expression leads to alterations in the coupling

117 Furthermore, our experiments show that progerin expression leads to enhanced nuclear shape fluc

118 Recently, we found that limiting progerin expression to vascular smooth muscle cells (VSM

119 The cellular consequences of progerin expression underlying the HGPS phenotype remain

120 senescence, while STXBP5 deletion suppressed progerin expression, delayed senility, and decreased the

121 nguishable from HGPSrev mice with ubiquitous progerin expression, in contrast with the ameliorated pr

122 early proliferative defects associated with progerin expression.

123 otein 5 (STXBP5) as an influencing factor of progerin expression.

124 HGPS mouse model with selective endothelial progerin expression.

125 ane proteins to identify proximal effects of progerin expression.

126 syndrome (HGPS) fibroblasts that express the Progerin form of lamin A, causing a major defect in nucl

127 Expression of a GFP-progerin fusion protein in normal fibroblasts caused a h

128 Circulating progerin has not been previously detected, precluding re

129 In addition, low levels of progerin have also been found in several tissues from no

130 STXBP5 and progerin have synergistic effects and a protein-protein

131 An ultrasensitive single-molecule counting progerin immunoassay was developed with prespecified per

132 ulation, validate the identification through progerin immunofluorescence, and demonstrate accurate su

133 On the molecular level, progerin impairs nucleocytoskeletal coupling in endothel

134 lted in abnormal nuclear localization of GFP-progerin in comparison with the localization pattern of

135 ions in keratinocyte nuclei, mice expressing progerin in epidermis had normal hair grown and wound he

136 We generated transgenic mice expressing progerin in epidermis under control of a keratin 14 prom

137 We found that expression of progerin in iPSC-derived fibroblasts and neurons induces

138 ese differences was uncovered; the amount of progerin in Lmna HG/LCO fibroblasts and tissues was lowe

139 The steady-state levels of progerin in LmnanHG/+ MEFs and tissues were lower, sugge

140 ice harboring the Lmna(HG-C) allele produced progerin in neurons, but they had no pathology in the ce

141 Mean plasma progerin in non-HGPS participants (n=69; 39 male, 30 fem

142 ously unidentified insights into the role of progerin in regulating the IGF-1R/Akt signaling in HGPS

143 The expression of progerin in SMCs resulted in the formation of an irregul

144 on-Gilford progeria syndrome), the levels of progerin in the brain were extremely low.

145 ults implicate the abnormal farnesylation of progerin in the cellular phenotype in HGPS cells and sug

146 lts support a model that the accumulation of progerin in the nuclear lamina leads to altered H3K27me3

147 Accumulation of progerin in the nuclei of HGPS cells impairs nuclear fun

148 Also, blocking farnesylation of authentic progerin in transiently transfected HeLa, HEK 293, and N

149 ng half-life and tissue-specific turnover of progerin in vivo.

150 The synthesis of progerin in wild-type fibroblasts was accompanied by the

151 ading to expression of truncated prelamin A (progerin) in the nucleus.

152 The expression of a mutant Lamin A, progerin, in Hutchinson-Gilford Progeria Syndrome leads

153 stably expressed lamin A mutants, including progerin, in otherwise identical primary human fibroblas

154 Thus, our study suggests that progerin-induced aging can be used to reveal late-onset

155 Furthermore, we demonstrated that progerin-induced apoptosis could be rescued by XPA, sugg

156 h in progeria, here, we investigated whether progerin-induced atherosclerosis is prevented in HGPSrev

157 ent of YAP/TAZ-targeting drugs to ameliorate progerin-induced atherosclerosis.

158 Assessing the reversibility of progerin-induced damage and the relative contribution of

159 e3, whereas lowering LAP2 levels exacerbates progerin-induced defects.

160 iously reported that XPA mislocalized to the progerin-induced DNA double-strand break (DSB) sites, bl

161 Our results propose a mechanism for progerin-induced genome instability and accelerated repl

162 ss seen in HGPS patients, our data show that progerin-induced impairment of mechanosignaling in endot

163 PS since increasing LAP2alpha levels rescues progerin-induced proliferation defects and loss of H3K27

164 Progerin-induced VSMC alterations promote EC dysfunction

165 The accumulation of progerin induces inflammation, cellular senescence and a

166 Although progerin induces significant alterations in keratinocyte

167 ernative splicing of the LMNA transcript, as progerin induction was suppressed by the singlet oxygen

168 Rather, Progerin inhibited Tpr import because transport of large

169 isplay elevated ROS, these data suggest that progerin inhibits nuclear transport via oxidative stress

170 Thus, plasma progerin is a biomarker for HGPS whose reduction enables

171 Progerin is a mutant form of lamin A responsible for Hut

172 Recent studies have demonstrated that progerin is also produced at low levels in normal human

173 This finding suggests that accumulation of progerin is directly involved in vascular disease in pro

174 Progerin is even more long lived than lamin A/C in the c

175 The induction of progerin is mediated by UVA-induced oxidative damage and

176 cts with lamin A, while its interaction with progerin is significantly reduced.

177 lthough benefit is much more pronounced when progerin is targeted in mice with mild symptoms.

178 Progerin is targeted to the nuclear envelope and causes

179 Progerin is targeted to the nuclear rim, where it interf

180 Accumulation of progerin is thought to underlie the pathophysiology of H

181 During interphase, irreversibly farnesylated progerin/LADelta50 anchors to the nuclear membrane and c

182 ng normal cells are binucleated, implicating progerin/LADelta50 as causing similar mitotic defects in

183 ermore, we demonstrate that small amounts of progerin/LADelta50 exist in normal fibroblasts, and a si

184 Here, we report that progerin/LADelta50 mislocalizes into insoluble cytoplasm

185 ing in a mutant lamin A (LA) protein termed "progerin/LADelta50" that lacks the normal cleavage site

186 Progerin/LADelta50's localization and behavior during mi

187 lasts, and a significant percentage of these progerin/LADelta50-expressing normal cells are binucleat

188 bitors or a farnesylation-incompetent mutant progerin/LADelta50.

189 itors with the ability to block pathological progerin-lamin A/C binding may represent a promising str

190 (JH1, JH4, and JH13) that efficiently block progerin-lamin A/C binding.

191 Expression of progerin leads to alterations in nuclear morphology, whi

192 We find that expression of progerin leads to inhibition of proliferation in a high

193 However, the mechanisms of how progerin leads to massive SMC loss are unknown.

194 Accumulation of progerin leads to various ageing-associated nuclear defe

195 Progerin levels did not differ by sex (P=0.99).

196 Progerin levels fell within 4 months of therapy and rema

197 n was developed and used to demonstrate high progerin levels in HGPS plasma that decreased with lonaf

198 roblasts transfected with these ASOs exhibit progerin levels similar to (or greater than) those in fi

199 splicing in HGPS cells and modestly lowered progerin levels.

200 For any given decrease in progerin, life expectancy incrementally increased with l

201 a gene-targeted allele yielding exclusively progerin (Lmna HG) and found that heterozygous mice (Lmn

202 nd knock-in allele yielding non-farnesylated progerin (Lmna(csmHG)) in which the carboxyl-terminal -C

203 showed that mice expressing non-farnesylated progerin (Lmna(nHG/+) mice, in which progerin's carboxyl

204 ated knockin mice expressing nonfarnesylated progerin (LmnanHG/+).

205 These findings lead us to propose that progerin may interfere with telomere structure or metabo

206 We speculate that oxidative stress caused by progerin may occur upstream or downstream of Ran, depend

207 ence, providing mechanistic insight into how progerin may participate in the normal aging process.

208 ing replication forks, PCNA sequestration by progerin may shift the equilibrium to favor XPA binding.

209 ersed the morphological abnormalities in the progerin meshwork and markedly reduced the frequency of

210 s of lamin B1 expression might normalize the progerin meshwork and prevent NM ruptures and blebs.

211 Of note, the progerin meshwork was markedly abnormal in nuclear blebs

212 mbled the irregularities and openings in the progerin meshwork.

213 Mechanistically, progerin mislocalizes outside of the nucleus, interacts

214 Progerin mRNA levels were robustly reduced in vivo, but

215 ed to oxidative stress resist the effects of progerin on Ran and Ubc9.

216 we find that expression in HeLa cells of GFP-progerin or an uncleavable form of prelamin A with a Zmp

217 Progerin overexpression increased levels of SUN1, which

218 r improve disease by additionally inhibiting progerin prenylation.

219 elationship between telomere dysfunction and progerin production during the induction of cell senesce

220 effect relationship between normal aging and progerin production in normal individuals has not yet be

221 Interestingly, elevated progerin production was not seen during cellular senesce

222 escence plays a causative role in activating progerin production.

223 Lamin A, lamin C, and progerin, products of the Lmna gene, have antagonistic f

224 cular calcification in normal aging, because progerin progressively accumulates in the vascular tissu

225 hances canonical LMNA splicing and decreases progerin protein levels in patient-derived cells.

226 tion of normal RNA splicing and reduction of progerin protein levels.

227 robustly reduced in vivo, but the extent of progerin protein reduction differed between tissues, sug

228 esulting in formation of the disease-causing progerin protein.

229 We found that progerin reduces the nuclear/cytoplasmic concentration o

230 SSIM progerin relocalized from the nuclear periphery into nuc

231 expression of LAP2alpha in cells expressing progerin restores proliferation and extracellular matrix

232 Progerin retains a farnesyl lipid anchor at its carboxyl

233 prelamin A in HGPS, which is commonly called progerin, retains the CAAX motif that triggers farnesyla

234 sylated progerin (Lmna(nHG/+) mice, in which progerin's carboxyl-terminal -CSIM motif was changed to

235 transferase inhibitor (FTI), suggesting that progerin's farnesyl lipid is important for disease patho

236 develop a plasma progerin assay to evaluate progerin's quantity, response to progerin-targeted thera

237 Progerin sequesters NRF2 and thereby causes its subnucle

238 Progerin sequestration of PCNA promotes replication fork

239 Without progerin-specific treatment, death occurs at an average

240 mitotic spindle assembly, as a regulator of progerin splicing.

241 progerin while lacking lamin A and allowing progerin suppression and lamin A restoration in a time-

242 Ubiquitous progerin suppression and lamin A restoration significant

243 and lifespan normalized in HGPSrev mice when progerin suppression and lamin A restoration were restri

244 -CreERT2 and HGPSrev-SM22alpha-Cre mice with progerin suppression in endothelial cells (ECs) and vasc

245 Our studies demonstrate that progerin suppression in VSMCs, but not in ECs, prevents

246 to evaluate progerin's quantity, response to progerin-targeted therapy, and relationship to patient s

247 n enables short- and long-term assessment of progerin-targeted treatment efficacy.

248 s from a dominant mutant form of prelamin A (progerin) that has an internal deletion of 50 aa near th

249 ome (HGPS) is caused by a mutant prelamin A, progerin, that terminates with a farnesylcysteine.

250 Association of progerin, the lamin A isoform responsible for the premat

251 The same ASO also reduced the expression of progerin, the mutant prelamin A protein in HGPS, in fibr

252 Progerin, the protein that causes Hutchinson-Gilford pro

253 Here we explore the relationship between progerin, the Ran GTPase, and oxidative stress.

254 that retention of the farnesyl group causes progerin to become permanently anchored in the nuclear m

255 es show that the ability of non-farnesylated progerin to elicit disease depends on the carboxyl-termi

256 n farnesylation would block the targeting of progerin to the nuclear envelope, and we further hypothe

257 Stable attachment of progerin to the nuclear membrane disrupts the Ran gradie

258 tachment of a mutant form of lamin A (termed progerin) to the nuclear membrane.

259 d that blocking farnesylation would decrease progerin toxicity.

260 01 provided the most significant decrease in progerin transcripts in patient fibroblasts.

261 el of HGPS produced significant reduction of progerin transcripts in the aorta, a particularly critic

262 knock-in allele, Lmna(HG-C), which produces progerin transcripts lacking an miR-9 binding site.

263 Progerin triggers loss of the heterochromatic marker H3K

264 A sensitive, quantitative immunoassay for progerin was developed and used to demonstrate high prog

265 This progerin was farnesylated, as judged by metabolic labeli

266 is hypothesis, the terminal CSIM sequence in progerin was mutated to SSIM, a sequence that cannot be

267 ted, truncated variant of prelamin A called "progerin." We surveyed the diffusional mobilities of nuc

268 alternatively spliced product of LMNA called progerin, which is also expressed in normal aged cells.

269 production of a truncated prelamin A, called progerin, which is farnesylated at its carboxyl terminus

270 e and knock-in Lmna(G609G/+) mice expressing progerin, which mimic the main clinical manifestations o

271 This mutation generates the lamin A variant progerin, which we show here leads to loss of LAP2alpha

272 t produces a mutant lamin A protein, termed "progerin," which carries a 50-aa deletion near its C ter

273 rev) mice engineered to ubiquitously express progerin while lacking lamin A and allowing progerin sup

274 We hypothesized that accumulation of progerin with abnormal nuclear shapes may also be accele

275 s cause an abnormal association of LADelta50/progerin with membranes during mitosis, which delays the

276 d LMNA mutation results in a protein, termed progerin, with an internal 50 amino acid deletion and, u

277 ation of the farnesylated prelamin A variant progerin, with an internal deletion including its proces

278 producing a truncated mutant protein termed "progerin." WT prelamin A is anchored to the nuclear enve