Progranulin polymorphism rs5848 is associated with increased risk of Alzheimer's disease

doi:10.1016/j.gene.2014.03.041

Gene

Volume 542, Issue 2, 1 June 2014, Pages 141-145

https://doi.org/10.1016/j.gene.2014.03.041 Get rights and content

Highlights

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It is the first meta-analysis on PGRN rs5848 SNP and AD.
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rs5848 is associated with increased risk of AD in homozygous and recessive models.
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TT allele of rs5848 is associated with increased risk of AD.
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This meta-analysis will be helpful in clarifying current controversies.

Abstract

Progranulin is the precursor of granulins, and its down-regulation leads to neurodegeneration. Recent studies have indicated an association of progranulin polymorphism rs5848 with Alzheimer's disease (AD) risk, but the results remain controversial. To verify the association between rs5848 and AD risk, we retrieved the published literature from PubMed and other databases, and performed a meta-analysis by pooling all five studies containing 2502 AD cases and 2162 controls. The results showed that rs5848 is associated with increased risk of AD in homozygous (TT vs. CC: OR, 1.36; 95% CI, 1.11–1.66; P = 0.003) and recessive models (TT vs. CC + CT: OR, 1.31; 95% CI, 1.08–1.58; P = 0.006). This association was remained in Caucasian (2227 cases and 1902 controls). Our data indicate that TT allele of rs5848 is associated with increased risk of AD, suggesting that genetic variant of progranulin gene may play an important role in AD development.

Introduction

Dementia is a symptom associated with serious loss of global cognitive ability. It is estimated that about 35.6 million people lived with dementia worldwide in 2010, however, the number is expected to almost double every 20 years, to 65.7 million in 2030 and 115.4 million in 2050 (Prince et al., 2013). As the most common disease leading to primary degenerative dementia, Alzheimer's disease (AD) is a multifactorial disorder with a complex etiology and a strong genetic component. Recently studies have found that about 20% of AD-attributable risk is related to the ε4 variant in apolipoprotein E (APOE) (Slooter et al., 1998). A series of large genome-wide association studies (GWASs) have identified several additional variants that affect AD susceptibility, including CR1, CLU, PICALM, BIN1, CD2AP, CD33, EPHA1, MS4A6A/MS4E4, and ABCA7 (reviewed in Piaceri et al., 2013). Recently, progranulin (PGRN) was identified as a susceptibility gene for neurodegenerative diseases (Fenoglio et al., 2009, Viswanathan et al., 2009). In particular, a single-nucleotide polymorphism (SNP) rs5848, located in the 3′-untranslated region (3′-UTR) of PGRN, is associated with AD and other neurodegenerative diseases (Rademakers et al., 2008). Several studies have reported that the T-allele of rs5848 is associated with the increased risk of AD (Kamalainen et al., 2013, Lee et al., 2011, Viswanathan et al., 2009), however, others failed to observe this association (Fenoglio et al., 2009, Mateo et al., 2013). This inconsistence might be due to the limited subjects included in each study as single study may be underpowered to estimate the effects of loci conferring small changes in disease risk. In the present study, we conducted a meta-analysis by pooling all five case–control studies comprising 2502 AD cases and 2162 controls to derive a more precise estimation of the relationship between the rs5848 and AD risk.

Section snippets

Identification and eligibility of relevant studies

We conducted a literature search in the PubMed databases up to July 2013 using the following MeSH terms and keywords: “progranulin polymorphism” or “rs5848”, and “Alzheimer's disease”. Additional studies were identified by a manual search from other sources (e.g., Web of Knowledge), references of original studies or review articles on this topic. Eligible studies included in this meta-analysis had to meet the following criteria: (a) evaluation of the association between rs5848 and AD, (b) an

Characteristics of studies

Fourteen abstracts were retrieved through the search key words “progranulin polymorphism” or “rs5848” and “Alzheimer's disease”, and four studies meeting the inclusion criteria were identified as eligible (Fenoglio et al., 2009, Kamalainen et al., 2013, Lee et al., 2011, Viswanathan et al., 2009). Out of the fourteen, one was a review article (Doi and Tanaka, 2013), one was to evaluate the association of rs5848 (3′ UTR variant in progranulin) with TDP-43 immunoreactivity (Dickson et al., 2010),

Discussion

The present study demonstrated that rs5848 polymorphism is associated with increased risk of AD in homozygous and recessive models, and this association is observed in Caucasians. PGRN is the precursor of granulins, and its down-regulation may lead to neurodegeneration (Baker et al., 2006, Cruts et al., 2006). It has been reported that rs5848 at the 3′-UTR of PGRN is the functional SNP relevant to PGRN expression and that miR-659 can regulate PGRN expression as miR-659 binds more efficiently to

Author contributions

All authors contributed to this study, JS, GC and ZX conceived and designed the experiments; JS, LS and GC performed the experiments and analyzed the data; GC and ZX contributed materials/analysis tools; JS GC and ZX wrote the paper.

Competing financial interests

The authors declare no competing financial interests.

Acknowledgments

We are grateful to Drs. Christine Van Broeckhoven and Kristel Sleegers, from University of Antwerp, Belgium for providing the frequencies of the rs5848 of subjects. This study was supported by the Fundamental Research Funds for the Central Universities (2011QNA7018, 2012QNA7019) and the Qianjiang Talents Program of Zhejiang Province (2013R10041). Dr. Guangdi Chen was supported by the Technology Foundation for Excellent Overseas Chinese Scholar, Zhejiang Province Human Resources and Social

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Heterozygous GRN (progranulin) mutations cause frontotemporal dementia (FTD) due to haploinsufficiency, and increasing progranulin levels is a major therapeutic goal. Several microRNAs, including miR-29b, negatively regulate progranulin protein levels. Antisense oligonucleotides (ASOs) are emerging as a promising therapeutic modality for neurological diseases, but strategies for increasing target protein levels are limited. Here, we tested the efficacy of ASOs as enhancers of progranulin expression by sterically blocking the miR-29b binding site in the 3′ UTR of the human GRN mRNA. We found 16 ASOs that increase progranulin protein in a dose-dependent manner in neuroglioma cells. A subset of these ASOs also increased progranulin protein in iPSC-derived neurons and in a humanized GRN mouse model. In FRET-based assays, the ASOs effectively competed for miR-29b from binding to the GRN 3′ UTR RNA. The ASOs increased levels of newly synthesized progranulin protein by increasing its translation, as revealed by polysome profiling. Together, our results demonstrate that ASOs can be used to effectively increase target protein levels by partially blocking miR binding sites. This ASO strategy may be therapeutically feasible for progranulin-deficient FTD as well as other conditions of haploinsufficiency.
Regulation of extracellular progranulin in medial prefrontal cortex
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Progranulin is a secreted pro-protein that has anti-inflammatory and neurotrophic effects and is necessary for maintaining lysosomal function. Mutations in progranulin (GRN) are a major cause of frontotemporal dementia. Most pathogenic GRN mutations cause progranulin haploinsufficiency, so boosting progranulin levels is a promising therapeutic strategy. Progranulin is constitutively secreted, then taken up and trafficked to lysosomes. Before being taken up from the extracellular space, progranulin interacts with receptors that may mediate anti-inflammatory and growth factor-like effects. Modifying progranulin trafficking is a viable approach to boosting progranulin, but progranulin secretion and uptake by cells in the brain is poorly understood and may involve distinct mechanisms from other parts of the body. Understanding the cell types and processes that regulate extracellular progranulin in the brain could provide insight into progranulin's mechanism of action and inform design of progranulin-boosting therapies. To address this question we used microdialysis to measure progranulin in interstitial fluid (ISF) of mouse medial prefrontal cortex (mPFC). Grn^+/− mice had approximately 50% lower ISF progranulin than wild-type mice, matching the reduction of progranulin in cortical tissue. Fluorescent in situ hybridization and immunofluorescence confirmed that microglia and neurons are the major progranulin-expressing cell types in the mPFC. Studies of conditional microglial (Mg-KO) and neuronal (N-KO) Grn knockout mice revealed that loss of progranulin from either cell type results in approximately 50% reduction in ISF progranulin. LPS injection (i.p.) produced an acute increase in ISF progranulin in mPFC. Depolarizing cells with KCl increased ISF progranulin, but this response was not altered in N-KO mice, indicating progranulin secretion by non-neuronal cells. Increasing neuronal activity with picrotoxin did not increase ISF progranulin. These data indicate that microglia and neurons are the source of most ISF progranulin in mPFC, with microglia likely secreting more progranulin per cell than neurons. The acute increase in ISF progranulin after LPS treatment is consistent with a role for extracellular progranulin in regulating inflammation, and may have been driven by microglia or peripheral immune cells. Finally, these data indicate that mPFC neurons engage in constitutive progranulin secretion that is not acutely changed by neuronal activity.
Preclinical Interventions in Mouse Models of Frontotemporal Dementia Due to Progranulin Mutations
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Heterozygous loss-of-function mutations in progranulin (GRN) cause frontotemporal dementia (FTD), a leading cause of early-onset dementia characterized clinically by behavioral, social, and language deficits. There are currently no FDA-approved therapeutics for FTD-GRN, but this has been an active area of investigation, and several approaches are now in clinical trials. Here, we review preclinical development of therapies for FTD-GRN with a focus on testing in mouse models. Since most FTD-GRN-associated mutations cause progranulin haploinsufficiency, these approaches focus on raising progranulin levels. We begin by considering the disorders associated with altered progranulin levels, and then review the basics of progranulin biology including its lysosomal, neurotrophic, and immunomodulatory functions. We discuss mouse models of progranulin insufficiency and how they have been used in preclinical studies on a variety of therapeutic approaches. These include approaches to raise progranulin expression from the normal allele or facilitate progranulin production by the mutant allele, as well as approaches to directly increase progranulin levels by delivery across the blood–brain barrier or by gene therapy. Several of these approaches have entered clinical trials, providing hope that new therapies for FTD-GRN may be the next frontier in the treatment of neurodegenerative disease.
Abnormal spatiotemporal expression pattern of progranulin and neurodevelopment impairment in VPA-induced ASD rat model
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Citation Excerpt :
PGRN may counteract synapse elimination to promote motor performance in the developing cerebellum (Uesaka et al., 2018). Mutations in the progranulin gene are causatively linked to pathology of neurodegenerative diseases, such as frontotemporal dementia and Alzheimer's disease (Mendsaikhan et al., 2019; Baker et al., 2006; Cruts et al., 2006; Kamalainen et al., 2013; Mackenzie et al., 2006; Sheng et al., 2014), and lead to age-dependent emergence of neurophysiological and behavioral abnormalities (Nagy et al., 2019) Furthermore, low plasma PGRN levels have been detected in children with autism (Al-Ayadhi and Mostafa, 2011) and decreased PGRN mRNA levels have also reported in prefrontal cortex and hippocampus of VPA-induced rat models of autism (Zhou et al., 2016). Based on previous studies, it is reasonable to speculate that PGRN has a pathogenic role in ASD.
Some environmental risk factors have been proven to contribute to the etiology of autism spectrum disorder (ASD). Exposure to the antiepileptic drug valproic acid (VPA) during pregnancy significantly increases the risk of ASD in humans, and consequently is utilized as a validated animal model of ASD in rodents; however, the precise molecular and cellular mechanisms remain ill-defined. In the present study, we investigated the effect of prenatal VPA exposure on the spatiotemporal dynamics of Progranulin (PGRN) expression, neuronal apoptosis, synapse density, and AKT/GSK-3β pathway activation in the brains of VPA-exposed offspring. Results from behavioral tests were consistent with prior studies showing impaired sociability, restricted interests and increased repetitive behaviors in VPA rats at postnatal days 28–32. Our data also indicated that VPA exposure resulted in abnormal dynamics of PGRN expression in different brain regions at the different development stages. The temporal and spatial patterns of PGRN expression were consistent with the spatiotemporal regularity of abnormalities, which observed in apoptosis-related protein levels, neuron numbers, dendritic spine density, synapse-related protein levels, and AKT/GSK-3β phosphorylation in VPA rats. It suggests that prenatal VPA exposure may affect the spatiotemporal regularity of neuronal apoptosis and synaptic development/regression via interfering with the spatiotemporal process of PGRN expression and downstream AKT/GSK-3β pathway activation. This may be a potential mechanism of the abnormal neuroanatomical changes and ASD-like behaviors in VPA-induced ASD.
Delivering progranulin to neuronal lysosomes protects against excitotoxicity
2021, Journal of Biological Chemistry
Loss-of-function mutations in progranulin (GRN) are a major genetic cause of frontotemporal dementia (FTD), possibly due to loss of progranulin’s neurotrophic and anti-inflammatory effects. Progranulin promotes neuronal growth and protects against excitotoxicity and other forms of injury. It is unclear if these neurotrophic effects are mediated through cellular signaling or through promotion of lysosomal function. Progranulin is a secreted proprotein that may activate neurotrophic signaling through cell-surface receptors. However, progranulin is efficiently trafficked to lysosomes and is necessary for maintaining lysosomal function. To determine which of these mechanisms mediates progranulin’s protection against excitotoxicity, we generated lentiviral vectors expressing progranulin (PGRN) or lysosome-targeted progranulin (L-PGRN). L-PGRN was generated by fusing the LAMP-1 transmembrane and cytosolic domains to the C-terminus of progranulin. L-PGRN exhibited no detectable secretion, but was delivered to lysosomes and processed into granulins. PGRN and L-PGRN protected against NMDA excitotoxicity in rat primary cortical neurons, but L-PGRN had more consistent protective effects than PGRN. L-PGRN’s protective effects were likely mediated through the autophagy-lysosomal pathway. In control neurons, an excitotoxic dose of NMDA stimulated autophagy, and inhibiting autophagy with 3-methyladenine reduced excitotoxic cell death. L-PGRN blunted the autophagic response to NMDA and occluded the protective effect of 3-methyladenine. This was not due to a general impairment of autophagy, as L-PGRN increased basal autophagy and did not alter autophagy after nutrient starvation. These data show that progranulin’s protection against excitotoxicity does not require extracellular progranulin, but is mediated through lysosomes, providing a mechanistic link between progranulin’s lysosomal and neurotrophic effects.
Lysosome dysfunction as a cause of neurodegenerative diseases: Lessons from frontotemporal dementia and amyotrophic lateral sclerosis
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Citation Excerpt :
For the most part, pathogenic GRN mutations cause pure FTD and are not thought to cause ALS (Cannon et al., 2013; Del Bo et al., 2011; Schymick et al., 2007; Yu et al., 2010). Beyond FTD, a common genetic variant in GRN, the T allele of rs5848, has been associated with an increased risk of developing AD (Lee et al., 2011; Sheng et al., 2014; Xu et al., 2017) and PD (Chang et al., 2013; Chen et al., 2015). Most pathogenic GRN mutations are small insertions, deletions, or duplications that affect the GRN reading-frame, splice-sites, or non-sense mutations, which lead to a premature stop codon and degradation of the GRN mRNA transcript (Nguyen et al., 2018a; Yu et al., 2010).
Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are fatal neurodegenerative disorders that are thought to exist on a clinical and pathological spectrum. FTD and ALS are linked by shared genetic causes (e.g. C9orf72 hexanucleotide repeat expansions) and neuropathology, such as inclusions of ubiquitinated, misfolded proteins (e.g. TAR DNA-binding protein 43; TDP-43) in the CNS. Furthermore, some genes that cause FTD or ALS when mutated encode proteins that localize to the lysosome or modulate endosome-lysosome function, including lysosomal fusion, cargo trafficking, lysosomal acidification, autophagy, or TFEB activity. In this review, we summarize evidence that lysosomal dysfunction, caused by genetic mutations (e.g. C9orf72, GRN, MAPT, TMEM106B) or toxic-gain of function (e.g. aggregation of TDP-43 or tau), is an important pathogenic disease mechanism in FTD and ALS. Further studies into the normal function of many of these proteins are required and will help uncover the mechanisms that cause lysosomal dysfunction in FTD and ALS. Mutations or polymorphisms in genes that encode proteins important for endosome-lysosome function also occur in other age-dependent neurodegenerative diseases, including Alzheimer's (e.g. APOE, PSEN1, APP) and Parkinson's (e.g. GBA, LRRK2, ATP13A2) disease. A more complete understanding of the common and unique features of lysosome dysfunction across the spectrum of neurodegeneration will help guide the development of therapies for these devastating diseases.

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View full text

Progranulin polymorphism rs5848 is associated with increased risk of Alzheimer's disease

Highlights

Abstract

Introduction

Section snippets

Identification and eligibility of relevant studies

Characteristics of studies

Discussion

Author contributions

Competing financial interests

Acknowledgments

Journal of the Neurological Sciences

Lancet Neurology

Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17

Nature

Operating characteristics of a rank correlation test for publication bias

Biometrics

Genetic variability in progranulin contributes to risk for clinically diagnosed Alzheimer disease

Neurology

Association between GRN rs5848 polymorphism and Parkinson's disease in Taiwanese population

PLoS One

Novel exon 1 progranulin gene variant in Alzheimer's disease

European Journal of Neurology

Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21

Nature

Common variant in GRN is a genetic risk factor for hippocampal sclerosis in the elderly

Neuro-Degenerative Diseases

The genetics of corticobasal syndrome

Brain and Nerve

Rs5848 variant influences GRN mRNA levels in brain and peripheral mononuclear cells in patients with Alzheimer's disease

Journal of Alzheimer's Disease

Systematic evaluation and comparison of statistical tests for publication bias

Journal of Epidemiology