Loss of progranulin function in frontotemporal lobar degeneration

Cruts, Marc; Broeckhoven, Christine Van

doi:10.1016/j.tig.2008.01.004

Cited by 110 publications

(83 citation statements)

References 91 publications

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“…In less than 4 years, more than 60 different pathogenetic mutations for GRN have been reported in literature (http:// www.molgen.ua.ac.be/FTDmutations). In the presence of GRN gene mutation, FTLD segregates in a Mendelian fashion, which is compatible with an autosomal dominant inheritance (Cruts and Van, 2008). The physiological role, as well as the effect of reduction of PGRN in the brain tissue are still largely unknown, although it has been recently suggested that PGRN might act as a neurotrophic factor (Van Damme et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Granulin mutation drives brain damage and reorganization from preclinical to symptomatic FTLD

Borroni

Alberici

Cercignani

et al. 2012

Neurobiology of Aging

102

112

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Granulin (GRN) mutations have been identified as a major cause of frontotemporal lobar degeneration (FTLD) by haploinsufficiency mechanism, although their effects on brain tissue dysfunction and damage still remain to be clarified. In this study, we investigated the pattern of neuroimaging abnormalities in FTLD patients, carriers and noncarriers of GRN Thr272fs mutation, and in presymptomatic carriers. We assessed regional gray matter (GM) atrophy, and resting (RS)-functional magnetic resonance imaging (fMRI). The functional connectivity maps of the salience (SN) and the default mode (DMN) networks were considered. Frontotemporal gray matter atrophy was found in all FTLD patients (more remarkably in those GRN Thr272fs carriers), but not in presymptomatic carriers. Functional connectivity within the SN was reduced in all FTLD patients (again more remarkably in those mutation carriers), while it was enhanced in the DMN. Conversely, presymptomatic carriers showed increased connectivity in the SN, with no changes in the DMN. Our findings suggest that compensatory mechanisms of brain plasticity are present in GRN-related FTLD, but with different patterns at a preclinical and symptomatic disease stage.

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Section: Introductionmentioning

confidence: 99%

Granulin mutation drives brain damage and reorganization from preclinical to symptomatic FTLD

Borroni

Alberici

Cercignani

et al. 2012

Neurobiology of Aging

102

112

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“…Although ϳ40% of FTLD patients are pathologically characterized by tau positive inclusions, the remaining patients present with tau and ␣-synuclein-negative, ubiquitin-positive nuclear or cytoplasmic inclusions [frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U)] (Mackenzie and Rademakers, 2007;Cruts and Van Broeckhoven, 2008). Deposited proteins observed in FTLD-U brains include the TAR-DNA binding protein 43 (Neumann et al, 2006)] and the fused in sarcoma protein [FUS (FTLD-FUS)] (Neumann et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

“…Deposited proteins observed in FTLD-U brains include the TAR-DNA binding protein 43 (Neumann et al, 2006)] and the fused in sarcoma protein [FUS (FTLD-FUS)] (Neumann et al, 2009). Genetic linkage studies and/or mutation screenings identified loss-of-function mutations in the progranulin gene (GRN ) in patients with familial FTLD-TDP (Baker et al, 2006;Cruts et al, 2006;Cruts and Van Broeckhoven, 2008;Gijselinck et al, 2008). Of the mutations reported to date (http:// www.molgen.vib-ua.be/FTDMutations/), most are loss-offunction mutations leading to GRN haploinsufficiency , which results in a severe reduction of GRN levels in tissues and biological fluids of patients (Ghidoni et al, 2008;Finch et al, 2009;Sleegers et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Rescue of Progranulin Deficiency Associated with Frontotemporal Lobar Degeneration by Alkalizing Reagents and Inhibition of Vacuolar ATPase

Capell¹,

Liebscher²,

Fellerer³

et al. 2011

J. Neurosci.

123

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Numerous loss-of-function mutations in the progranulin (GRN) gene cause frontotemporal lobar degeneration with ubiquitin and TAR–DNA binding protein 43-positive inclusions by reduced production and secretion of GRN. Consistent with the observation that GRN has neurotrophic properties, pharmacological stimulation of GRN production is a promising approach to rescueGRNhaploinsufficiency and prevent disease progression. We therefore searched for compounds capable of selectively increasing GRN levels. Here, we demonstrate that four independent and highly selective inhibitors of vacuolar ATPase (bafilomycin A1, concanamycin A, archazolid B, and apicularen A) significantly elevate intracellular and secreted GRN. Furthermore, clinically used alkalizing drugs, including chloroquine, bepridil, and amiodarone, similarly stimulate GRN production. Elevation of GRN levels occurs via a translational mechanism independent of lysosomal degradation, autophagy, or endocytosis. Importantly, alkalizing reagents rescue GRN deficiency in organotypic cortical slice cultures from a mouse model for GRN deficiency and in primary cells derived from human patients withGRNloss-of-function mutations. Thus, alkalizing reagents, specifically those already used in humans for other applications, and vacuolar ATPase inhibitors may be therapeutically used to prevent GRN-dependent neurodegeneration.

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“…PGRN plays a role in a variety of physiological and pathological processes including embryogenesis, inflammation, and tumor development (1). One of the best-described roles for PGRN regarding human pathologies is its capability to cause frontotemporal dementia (2). Secreted PGRN is proteolytically cleaved into subunits called granulins (GRNs) with different effects on inflammation than the precursor protein (3).…”

Section: Introductionmentioning

confidence: 99%

Circulating progranulin levels in women with gestational diabetes mellitus and healthy controls during and after pregnancy

Todoric

Handisurya

Perkmann

et al. 2012

European Journal of Endocrinology

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Objective: Progranulin (PGRN) was recently introduced as a novel marker of chronic inflammatory response in obesity and type 2 diabetes capable of directly affecting the insulin signaling pathway. This study aimed to investigate the role of PGRN in gestational diabetes mellitus (GDM), which is regarded as a model for early type 2 diabetes. Methods: PGRN serum levels were measured in 90 pregnant women (45 GDM and 45 normal glucose tolerance (NGT)). In addition, PGRN was measured during a 2-h, 75 g oral glucose tolerance test in 20 pregnant women (ten GDM and ten NGT) and in 16 of them post partum (ten GDM and six NGT). Results: PGRN concentrations were significantly higher in pregnant women compared with post partum levels (536.79G31.81 vs 241.53G8.86, P!0.001). Multivariate regression analyses showed a strong positive correlation of PGRN with estrogen and progesterone. The insulinogenic index, a marker of early insulin secretion, displayed a positive correlation with PGRN, both during and after pregnancy (RZ0.47, PZ0.034; RZ0.63, PZ0.012). HbA1c and the oral glucose insulin sensitivity index showed significant post partum associations with PGRN (RZ0.43, PZ0.049; RZK0.65, PZ0.009). Conclusions: PGRN concentrations are markedly lower after pregnancy regardless of the gestational glucose tolerance state. PGRN levels per se do not discriminate between mild GDM and NGT in pregnant women. Therefore, the development of GDM appears to be due to impaired b-cell function that is not related to PGRN effect.

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Loss of progranulin function in frontotemporal lobar degeneration

Cited by 110 publications

References 91 publications

Granulin mutation drives brain damage and reorganization from preclinical to symptomatic FTLD

Granulin mutation drives brain damage and reorganization from preclinical to symptomatic FTLD

Rescue of Progranulin Deficiency Associated with Frontotemporal Lobar Degeneration by Alkalizing Reagents and Inhibition of Vacuolar ATPase

Circulating progranulin levels in women with gestational diabetes mellitus and healthy controls during and after pregnancy

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