ライフサイエンスコーパス: progranulin

1 sulting from mutations in GRN (which encodes progranulin).

2 expression increases intracellular levels of progranulin.

3 ntia: microtubule-associated protein tau and progranulin.

4 in rat primary cortical neurons treated with progranulin.

5 ytosis of amyloid beta1-42 when treated with progranulin.

6 nd are required for the efficient ER exit of progranulin.

7 e and cytosolic domains to the C-terminus of progranulin.

8 erived neurons lacking the lysosomal protein progranulin.

9 ases, is a functional signaling receptor for progranulin.

10 to 18.8 pg/mL; P = .56), cerebrospinal fluid progranulin (0.42 pg/mL per day; 95% CI, -0.12 to 0.95 p

11 d by haploinsufficiency in the gene encoding progranulin(1,2).

12 and well tolerated but did not affect plasma progranulin (4.3 pg/mL per day change after treatment; 9

13 h caused significant reductions in uptake of progranulin, a molecular determinant for frontotemporal

14 All cause haploinsufficiency of progranulin, a protein involved in inflammation, tissue

15 t membranes and cell surfaces, we identified progranulin, a secreted growth factor, as a strong inter

16 s of function mutations in the gene encoding progranulin, a secreted growth factor.

17 FTD is highly heritable with mutations in progranulin accounting for 5-26% of cases in different p

18 he growth factor proepithelin (also known as progranulin, acrogranin, PC-derived growth factor, or gr

19 These data demonstrate that progranulin acts as a chemoattractant in the brain to re

20 Moreover, progranulin alone was sufficient to promote migration of

21 Adeno-associated virus-progranulin also corrected lysosomal abnormalities in Gr

22 ndent mechanism driven by macrophage-derived progranulin and cancer cell-secreted leukaemia inhibitor

23 n specific genetic forms of FTD, measures of progranulin and dipeptide repeat proteins in biofluids h

24 Notably, both progranulin and domain V stimulated the growth of adrena

25 for such a receptor, providing insight into progranulin and EphA2 signaling.

26 N) haploinsufficiency have reduced levels of progranulin and exhibit dysregulation in inflammatory an

27 Progranulin and granulins are attributed with roles in c

28 <0.01), and MMP-13 (r = 0.788, P <0.01); and progranulin and IL-8 (r = 0.762, P <0.01), MMP-8 (r = 0.

29 ls, but also the balance between full-length progranulin and its cleavage products, is important in r

30 601 mRNAs were changed (including Fus (Tls), progranulin and other transcripts encoding neurodegenera

31 urf4 is critical for the efficient export of progranulin and prosaposin from the ER.

32 quent lysosomal delivery of newly translated progranulin and prosaposin.

33 nvestigated the molecular nature of secreted progranulin and provide evidence that progranulin exists

34 The relationship between progranulin and TDP-43 and their respective roles in neu

35 nvolving microtubule-associated protein tau, progranulin and TDP-43, potential disease-modifying ther

36 ade in understanding the normal functions of progranulin and TDP-43, the molecular interactions betwe

37 ced signaling, or deleting expression of the progranulin and TMEM106B lysosomal proteins, did not alt

38 MAPT/tau, GRN/progranulin, and C9ORF72 have emerged as common FTD gene

39 RF72 from subjects with mutations in tau and progranulin, and from sporadic frontotemporal dementia.

40 Microglia produce high levels of progranulin, and reduction of progranulin in microglia a

41 tibodies in the CSF, but none developed anti-progranulin antibodies.

42 causing impaired production or secretion of progranulin are a common Mendelian cause of FTLD-TDP; ad

43 Inhibition of progranulin binding to sortilin, its main receptor, can

44 we identify and functionally characterize a progranulin [Biomphalaria glabrata granulin (BgGRN)] fro

45 These data support the concept of progranulin-boosting therapies for frontotemporal dement

46 Recombinant progranulin bound with high affinity to EphA2 in both so

47 Cell surface receptors for progranulin, but not granulin peptides, have been report

48 "Hit" genes regulated progranulin by transcriptional or posttranscriptional me

49 Additionally, recombinant progranulin can be intermolecularly cross-linked, yieldi

50 Furthermore, ECM1 and progranulin chondrogenic growth factor constitute an int

51 ing to a dimer ( approximately 180 kDa), and progranulins containing different epitope tags physicall

52 poral dementia and it is unclear if boosting progranulin could correct pre-existing deficits.

53 We found progranulin deficiency in neurons increased autophagy an

54 Thus, progranulin deficiency induced FTD-like behavioral and n

55 in global Grn+/- mice, showing that neuronal progranulin deficiency is sufficient to disrupt social b

56 ficits and suggesting an important effect of progranulin deficiency on neurons.

57 e single-nucleus RNA sequencing to show that progranulin deficiency promotes microglial transition fr

58 r, homozygous GRN mutations causing complete progranulin deficiency were recently shown to cause a di

59 consequences, of neurodegeneration caused by progranulin deficiency.

60 lt (DB-cAMP) as two phenotypic modulators of progranulin deficiency.

61 n of autofluorescent material was present in Progranulin deficient mice at 12 months.

62 Retinas of both wild-type and Progranulin deficient mice were examined by immunostaini

63 AMP also rescued cell cycle abnormalities in progranulin-deficient cells.

64 inal neurodegeneration as a new phenotype in progranulin-deficient FTLD, and suggest a pathological l

65 Both neuronal progranulin-deficient lines developed social dominance d

66 Bone marrow transplant of progranulin-deficient mice conditioned with busulfan and

67 Eighteen-month-old progranulin-deficient mice demonstrated impaired spatial

68 In this study, we showed that progranulin-deficient mice displayed increased depressio

69 In addition to behavioral deficits, progranulin-deficient mice showed a progressive developm

70 -related deficits, we generated two neuronal progranulin-deficient mouse lines using CaMKII-Cre and N

71 ulation of these pathways restored levels in progranulin-deficient neurons and reversed FTLD phenotyp

72 Augmented expression of Ran in progranulin-deficient neurons restores nuclear TDP-43 le

73 Limitations of current progranulin-enhancing strategies necessitate the discove

74 We conclude that circulating progranulin exists as a dimer and is not likely a compon

75 creted progranulin and provide evidence that progranulin exists as a homodimer.

76 cells of patients with FTD-GRN, resulted in progranulin expression and improvement of lipofuscin, ly

77 tested the efficacy of ASOs as enhancers of progranulin expression by sterically blocking the miR-29

78 ulin haploinsufficiency, therefore, boosting progranulin expression from the intact allele is a ratio

79 following findings: (1) confirmation of high progranulin expression levels in peripheral blood; (2) t

80 ted (including in sortilin, the receptor for progranulin) following depletion of TDP-43 from mouse ad

81 subjected to increased circulating levels of progranulin for 20 weeks.

82 PI may be due to protection of growth factor progranulin from enzymatic cleavage or suppression of CR

83 Mutations in the progranulin gene (GRN) are a major cause of frontotempor

84 Mutations in the progranulin gene (GRN) are an important cause of frontot

85 Loss-of-function mutations in the progranulin gene (GRN) cause frontotemporal lobar degene

86 Mutations in the progranulin gene (GRN) causing impaired production or se

87 Mutations in the progranulin gene (GRN) have recently been identified as

88 The progranulin gene (GRN) is mutated in 5-10% of patients w

89 Mutations in the progranulin gene (PGRN) have been shown to cause familia

90 Mutations in the Progranulin gene (PGRN) recently have been discovered to

91 ingle-copy loss-of-function mutations in the progranulin gene (PGRN) underlie the neurodegenerative d

92 Null mutations in the progranulin gene (PGRN) were recently reported to cause

93 been reported to carry null mutations in the progranulin gene (PGRN).

94 Mutations in the progranulin gene are a major cause of familial frontotem

95 Mutations in the progranulin gene are known to cause diverse clinical syn

96 Complete loss of the progranulin gene did not worsen TDP-43 toxicity, whereas

97 emporal lobar degeneration, mutations in the progranulin gene may be a risk factor for AD clinical ph

98 We describe 2 patients with progranulin gene mutations and evidence of Alzheimer dis

99 Progranulin gene polymorphisms are linked to Alzheimer's

100 Mutations in the human progranulin gene resulting in protein haploinsufficiency

101 Molecular pathways enriched in the progranulin gene set included cell adhesion and cell mot

102 ygous loss-of-function mutations in GRN, the progranulin gene, are a common genetic cause of the diso

103 rotubule Associated Protein Tau (MAPT) 34 in Progranulin (GRN) and 45 in Chromosome 9 Open Reading Fr

104 with FTD, although until recently only two [progranulin (GRN) and microtubule-associated protein tau

105 Progranulin (GRN) and TMEM106B are associated with sever

106 Loss-of-function mutations in progranulin (GRN) are a major genetic cause of frontotem

107 Loss-of-function mutations in progranulin (GRN) cause ubiquitin- and TAR DNA-binding p

108 Haploinsufficiency in the progranulin (GRN) gene accounts for 10% of all cases of

109 Mutations in the human progranulin (GRN) gene are a leading cause of frontotemp

110 Mutations in the progranulin (GRN) gene are responsible for 20% of famili

111 Mutations in the progranulin (GRN) gene have recently been reported as a

112 subgroup analyses based on brain region and progranulin (GRN) gene status.

113 eration (FTLD) is caused by mutations in the progranulin (GRN) gene.

114 Progranulin (GRN) haploinsufficiency is a frequent cause

115 Haploinsufficiency of progranulin (GRN) is a major genetic risk factor for fro

116 Recent studies suggest progranulin (GRN) is a neurotrophic factor.

117 ciency in frontotemporal dementia (FTD) gene progranulin (Grn) leads to an age-dependent, progressive

118 neration showed linkage to the region of the progranulin (GRN) locus and a homozygous mutation was de

119 Progranulin (GRN) loss-of-function mutations leading to

120 l Lobar Degeneration (FTLD) known stems from Progranulin (GRN) mutation and exhibits TDP-43 plus ubiq

121 h TDP-43 pathology (FTLD-TDP), especially in progranulin (GRN) mutation carriers.

122 Loss-of-function progranulin (GRN) mutations are a dominant cause of fron

123 Progranulin (GRN) mutations cause frontotemporal dementi

124 Progranulin (GRN) mutations causing haploinsufficiency a

125 sk of FTLD-TDP was observed in patients with progranulin (GRN) mutations.

126 hromosome 9 open reading frame 72 (C9orf72), progranulin (GRN) or microtubule-associated protein tau

127 Loss-of-function mutations in progranulin (GRN), a secreted glycoprotein expressed by

128 ariants of several of these genes, including progranulin (GRN), are causes of autosomal-dominant form

129 tic mutations usually in one of three genes: progranulin (GRN), microtubule-associated protein tau (M

130 Mutations in the gene encoding progranulin (GRN), which lead to reduced progranulin lev

131 dochondral ossification via associating with progranulin growth factor.

132 ate that FTD-related deficits resulting from progranulin haploinsufficiency can develop in the absenc

133 Mutations resulting in progranulin haploinsufficiency cause disease in patients

134 Progranulin haploinsufficiency causes frontotemporal dem

135 of the disorder, but the mechanisms by which progranulin haploinsufficiency causes neuronal dysfuncti

136 in a premature termination codon (PTC), thus progranulin haploinsufficiency has been proposed as a ma

137 ght to cause frontotemporal dementia through progranulin haploinsufficiency, therefore, boosting prog

138 GRN mutations cause progranulin haploinsufficiency, which eventually leads t

139 in heterozygous (Grn(+/-)) mice, which model progranulin haploinsufficiency.

140 Although recombinant progranulin has a molecular mass of approximately 85 kDa

141 Progranulin has also been implicated in cell growth, wou

142 gene did not worsen TDP-43 toxicity, whereas progranulin heterozygosity did.

143 Here, we studied progranulin heterozygous (Grn(+/-)) mice, which model pr

144 At 3 months, visfatin, progranulin, IL-8, and MMP-8 levels were significantly d

145 mutations and suggests a potential role for progranulin in Alzheimer's disease.

146 Localized lentiviral expression of progranulin in C57BL/6 mice resulted in an increase of I

147 derstanding the underlying mode of action of progranulin in cancer progression, tumor angiogenesis, a

148 ndogenous neuronal TMEM106B colocalizes with progranulin in late endo-lysosomes, and TMEM106B overexp

149 ghlight an important role for neuron-derived progranulin in maintaining normal social function.

150 high levels of progranulin, and reduction of progranulin in microglia alone is sufficient to recapitu

151 on chromatography, we found no evidence that progranulin in mouse or human plasma is a component of H

152 xo4- and Stat3-dependent IL-10 production by progranulin in regulatory T cells restrains inflammatory

153 ts uncover a previously unrecognized role of progranulin in suppressing aberrant microglia activation

154 Moreover, a reduction in progranulin in tau transgenic mice is associated with in

155 nditioned with busulfan and PLX3397 restored progranulin in the brain and eyes and normalized brain l

156 ration; however, the biological functions of progranulin in the brain remain unknown.

157 To further test the role of neuronal progranulin in the development of frontotemporal dementi

158 adeno-associated virus-driven expression of progranulin in the medial prefrontal cortex reverses soc

159 We have characterized the normal function of progranulin in the nematode Caenorhabditis elegans.

160 CSF progranulin increased after PR006 treatment in all patie

161 after PR006 treatment in all patients; blood progranulin increased in most patients but only transien

162 eduction of cellular sortilin expression and progranulin-induced breast cancer stem cell propagation.

163 In addition, inhibition of progranulin-induced mammosphere formation was examined a

164 ng to sortilin, its main receptor, can block progranulin-induced metastatic breast cancer using a tri

165 , targeting microglial dysfunction caused by progranulin insufficiency represents a potential therape

166 In this study, we discover that progranulin interactions with prosaposin, another lysoso

167 Visfatin, chemerin, progranulin, interleukin (IL)-1beta, IL-8, MMP-8, and MM

168 isease, this suggests that the processing of progranulin into granulins should be considered as part

169 Progranulin is a secreted glycoprotein, and the GRN gene

170 Progranulin is a secreted protein with roles in tumorige

171 Progranulin is cleaved into smaller peptides called gran

172 Human progranulin is comprised of multiple cysteine-rich, biol

173 the intracellular functions of granulins and progranulin is crucial for understanding their contribut

174 els in these lines indicated that most brain progranulin is derived from neurons.

175 However, progranulin is efficiently trafficked to lysosomes and i

176 Progranulin is involved in endocytosis, secretion and ly

177 Therefore, whether progranulin is involved in recruitment of immune cells i

178 Although progranulin is involved in wound healing, inflammation,

179 Progranulin is proteolytically processed into granulins,

180 neurons, suggesting that restoring neuronal progranulin is sufficient to correct deficits in Grn+/-

181 Granulin (GRN, or progranulin) is a protein involved in wound repair, infl

182 Granulin-epithelin precursor (GEP/progranulin) is an autocrine growth factor for ovarian c

183 PC cell-derived growth factor, also known as progranulin, is an M(r) 88,000 growth factor (referred a

184 Progranulin itself regulates lysosome function.

185 Homozygous progranulin knock-out (Grn(-/-)) mice have been studied

186 ise, we found that macrophages cultured from progranulin KO mice displayed enhanced rates of apoptoti

187 e understanding of the genetic regulation of progranulin levels and identify potential targets to tre

188 ipheral blood; (2) two subjects with reduced progranulin levels and mutations in the PGRN gene confir

189 , QRS interval) were unaffected by increased progranulin levels and no arrhythmogenic events were obs

190 Mechanisms controlling progranulin levels are largely unknown.

191 r data link the ALP to neuronal progranulin: progranulin levels are regulated by autophagy and, in tu

192 We identified 830 genes that raise or lower progranulin levels by at least 1.5-fold in Neuro2a cells

193 Restoring progranulin levels by targeting genetic modifiers revers

194 Deficient progranulin levels cause dose-dependent neurological syn

195 rtical neurons; several of these also raised progranulin levels in FTLD model mouse neurons.

196 , 33 genes of the druggable genome increased progranulin levels in mouse primary cortical neurons; se

197 Despite the critical role of progranulin levels in neurodegenerative disease risk, al

198 and identified specific pathways controlling progranulin levels in neurons.

199 sed platform to discover genes that regulate progranulin levels in neurons.

200 bitors have been repeatedly shown to elevate progranulin levels in preclinical models.

201 Measuring progranulin levels in these lines indicated that most br

202 D) due to haploinsufficiency, and increasing progranulin levels is a major therapeutic goal.

203 d abnormally enlarged lysosomes and boosting progranulin levels restored autophagy and lysosome size

204 Although elevation of secreted progranulin levels through a post-transcriptional mechan

205 ing progranulin (GRN), which lead to reduced progranulin levels, are a significant cause of familial

206 these studies suggest that not only absolute progranulin levels, but also the balance between full-le

207 ng a key role for this pathway in regulating progranulin levels.

208 inosis, suggesting that the total absence of progranulin may have effects distinct from those of hapl

209 at abnormal metabolism of TDP-43 mediated by progranulin may play a pivotal role in neurodegeneration

210 r than or in addition to loss of full-length progranulin, may contribute to disease in TDP-43 protein

211 The plasma progranulin measurement, which is predictive of GRN muta

212 We report that progranulin mediates proteolytic cleavage of TDP-43 to g

213 cover from damage or injury are destroyed in progranulin mutants, which in turn facilitates disease p

214 FTD-TDP) and to modify disease penetrance in progranulin mutation carriers (FTD-GRN).

215 ffered across subjects with C9ORF72, tau and progranulin mutations and sporadic frontotemporal dement

216 on case reports of 2 unrelated patients with progranulin mutations at the University of California, S

217 Many FTD-causing non-sense progranulin mutations contain a premature termination co

218 Progranulin mutations result in frontotemporal dementia,

219 vidual variation; however, within this group progranulin mutations were associated with strongly asym

220 Progranulin mutations were identified as a major cause o

221 sion was significantly more symmetrical than progranulin mutations with significantly less temporal l

222 mutations, 25 with tau mutations and 12 with progranulin mutations) and 20 sporadic subjects with beh

223 temporoparietal atrophy was associated with progranulin mutations.

224 clinical features in cases with and without progranulin mutations.

225 Heterozygous GRN (progranulin) mutations cause frontotemporal dementia (FT

226 ur groups: 1) familial FTD with mutations in progranulin (n = 36), valosin-containing protein (n = 5)

227 ported in subjects with mutations in tau and progranulin, no imaging features have been published in

228 overy of a functional signaling receptor for progranulin offers a new avenue for understanding the un

229 eased circulating levels of the glycoprotein progranulin on the development of supraventricular arrhy

230 Here, we aimed to test the effect of progranulin overexpression on cell-based tumorigenicity

231 hocardiography after 20 weeks of circulating progranulin overexpression.

232 Although progranulin partially co-fractionated with high density

233 at white matter involvement may be linked to progranulin pathological processes in a subset of GRN mu

234 expression of TMEM106B, which in turn alters progranulin pathways.

235 Thus, progranulin/perlecan interaction could contribute to a f

236 Heterozygous mutations in the gene encoding progranulin (PGRN) are a common genetic cause of FTD.

237 Heterozygous mutations in progranulin (PGRN) cause familial FTD and result in decr

238 within the granulin (GRN) gene that encodes progranulin (PGRN) cause the neurodegenerative disease f

239 Haploinsufficiency of progranulin (PGRN) due to mutations in the granulin (GRN

240 Haploinsufficiency of the progranulin (PGRN) gene (GRN) causes familial frontotemp

241 ave been identified in familial cases in the progranulin (PGRN) gene, also on chromosome 17q21.

242 milial FTDP associated with mutations in the progranulin (PGRN) gene, particularly in those cases wit

243 the presence of mutations in tau (MAPT) and progranulin (PGRN) genes.

244 Progranulin (PGRN) haploinsufficiency resulting from los

245 auses of FTD, near ubiquitously resulting in progranulin (PGRN) haploinsufficiency.

246 The growth factor progranulin (PGRN) has been implicated in embryonic deve

247 Loss-of-function mutations of progranulin (PGRN) have been linked to frontotemporal de

248 Progranulin (PGRN) is a secreted glycoprotein expressed

249 Progranulin (PGRN) is a widely expressed protein involve

250 Progranulin (PGRN) is a widely expressed secreted protei

251 Progranulin (PGRN) is involved in wound repair, inflamma

252 Progranulin (PGRN) is known to have anti-inflammatory ac

253 We screened total-blood progranulin (PGRN) levels in 107 patients with neurodege

254 aploinsufficiency and diminished function of progranulin (PGRN) protein, are strongly linked to FTLD

255 Progranulin (PGRN) restrains inflammation and is therape

256 hese families, FTD is caused by mutations in progranulin (PGRN) that are likely to create null allele

257 ii) PSAP, essential for GCase activation and progranulin (PGRN) transport; and (iii) PGRN, impacting

258 Haploinsufficiency of Progranulin (PGRN), a gene encoding a secreted glycoprot

259 oral dementia (GRN-FTD) due to deficiency in progranulin (PGRN), a lysosomal and secreted protein wit

260 Here, we show that reduction of progranulin (PGRN), a lysosomal protein associated with

261 Sortilin 1 regulates the levels of brain progranulin (PGRN), a neurotrophic growth factor that, w

262 Progranulin (PGRN), a pleiotrophic growth factor, is kno

263 Progranulin (PGRN), a secreted growth factor, is a key r

264 By studying mice lacking progranulin (PGRN), the protein encoded by GRN, we disco

265 rozygous mutations in GRN, the gene encoding progranulin (PGRN), were identified in patients with fro

266 Haploinsufficiency of the progranulin (PGRN)-encoding gene (GRN) causes frontotemp

267 ients with GRN mutations and in mice lacking progranulin (PGRN).

268 Our data link the ALP to neuronal progranulin: progranulin levels are regulated by autopha

269 (GRN) loss-of-function mutations leading to progranulin protein (PGRN) haploinsufficiency are preval

270 egfa and Grn mRNAs and may ultimately affect progranulin protein content, whereas FUS does not affect

271 A subset of these ASOs also increased progranulin protein in iPSC-derived neurons and in a hum

272 To investigate the influence of a decline in progranulin protein on other forms of neurodegenerative-

273 ar subcellular localization as the wild-type progranulin protein.

274 chanism that leads to the loss of functional progranulin protein.

275 herapeutic avenue for familial FTD caused by progranulin PTC mutations.

276 and gentamicin rescued the expression of the progranulin R493X mutation.

277 al dementia, we observed >70% readthrough of progranulin R493X with a suppressor tRNA that represente

278 The progranulin readthrough protein displayed similar subcel

279 Our data suggest that progranulin reduction might be the cause of multiple pro

280 rapeutics development.SIGNIFICANCE STATEMENT Progranulin regulates neuron and immune functions and is

281 els are regulated by autophagy and, in turn, progranulin regulates the ALP.

282 To better understand progranulin regulation, we performed a genome-wide RNAi

283 tional contributions relative to full-length progranulin remain unclear.

284 oral dementia (FTD), possibly due to loss of progranulin's neurotrophic and anti-inflammatory effects

285 In plasma, progranulin similarly forms complexes of approximately 1

286 eneration, including TDP-43 itself, FUS/TLS, progranulin, Tau, and ataxin 1 and -2.

287 Within progranulin, the subdomains interacting most with perlec

288 first report of a small molecule enhancer of progranulin transcription.

289 ut not inflammation were also increased from progranulin-treated primary neurons.

290 effect on sortilin cell surface abundance or progranulin uptake, suggesting specificity for NSG1 in t

291 ress with mouse models based on tau, TDP-43, progranulin, VCP, and CHMP2B.

292 The adeno-associated virus-progranulin vector only transduced neurons, suggesting t

293 Although the growth factor progranulin was discovered more than two decades ago, th

294 Progranulin was present within proliferating blood vesse

295 mediated overexpression of full-length mouse progranulin was used to increase plasma protein levels a

296 Increased circulating levels of progranulin were maintained throughout the 20-week study

297 n our model, increased levels of circulating progranulin were not sufficient to induce changes in car

298 ore, we found an autoregulatory mechanism of progranulin whereby a feed-forward loop occurred in an E

299 Interaction of progranulin with EphA2 caused prolonged activation of th

300 The interaction of progranulin with perlecan domain V involved the first tw