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1.  HUMAN GENETICS AS A TOOL TO IDENTIFY PROGRANULIN REGULATORS 
Journal of Molecular Neuroscience  2011;45(3):532-537.
Frontotemporal lobar degeneration (FTLD) is a common neurodegenerative disorder that predominantly affects individuals under the age of 65. It is known that the most common pathological subtype is FTLD with TAR DNA-binding protein 43 inclusions (FTLD-TDP). FTLD has a strong genetic component with about 50% of cases having a positive family history. Mutations identified in the progranulin gene (GRN) have been shown to cause FTLD-TDP as a result of progranulin haploinsufficiency. These findings suggest a progranulin-dependent mechanism in this pathological FTLD subtype. Thus, identifying regulators of progranulin levels is essential for new therapies and treatments for FTLD and related disorders. In this review, we discuss the role of genetic studies in identifying progranulin regulators, beginning with the discovery of pathogenic GRN mutations and additional GRN risk variants. We also cover more recent genetic advances, including the detection of variants in the transmembrane protein 106 B gene that increase FTLD-TDP risk presumably by modulating progranulin levels and the identification of a potential progranulin receptor, sortilin. This review highlights the importance of genetic studies in the context of FTLD and further emphasizes the need for future genetic and cell biology research to continue the effort in finding a cure for progranulin-related diseases.
doi:10.1007/s12031-011-9554-y
PMCID: PMC3310391  PMID: 21626010
progranulin; genetics; FTLD; TDP-43; TMEM106B; sortilin
2.  Progranulin: An emerging target for FTLD therapies 
Brain research  2012;1462:118-128.
Frontotemporal lobar degeneration (FTLD), a neurodegenerative disease primarily affecting the frontal and temporal lobes, is one of the most common types of dementia. While the majority of FTLD cases are sporadic, approximately 10–40% of patients have an inherited form of FTLD. Mutations in the progranulin gene (GRN) have recently been identified as a major cause of FTLD with ubiquitin positive inclusions (FTLD-U). Because over 70 disease-linked GRN mutations cause abnormal deficiencies in the production of PGRN, a protein that plays a crucial role in embryogenesis, cell growth and survival, as well as wound repair and inflammation, researchers now aim to design therapies that would increase PGRN levels in affected individuals, thereby alleviating the symptoms associated with disease. Several compounds and genetic factors, as well as PGRN receptors, have recently been identified because of their ability to regulate PGRN levels. Strict quality control measures are needed given that extreme PGRN levels at either end of the spectrum – too low or too high – can lead to neurodegeneration or cancer, respectively. The aim of this review is to highlight what is known regarding PGRN biology; to improve understanding of the mechanisms involved in regulating PGRN levels and highlight studies that are laying the groundwork for the development of effective therapeutic modulators of PGRN.
doi:10.1016/j.brainres.2012.01.047
PMCID: PMC3647886  PMID: 22338605
Progranulin; neurodegeneration; frontotemporal lobar degeneration; dementia; neurotrophic factors; sortilin
3.  Progranulin modulates zebrafish motoneuron development in vivo and rescues truncation defects associated with knockdown of Survival motor neuron 1 
Background
Progranulin (PGRN) encoded by the GRN gene, is a secreted glycoprotein growth factor that has been implicated in many physiological and pathophysiological processes. PGRN haploinsufficiency caused by autosomal dominant mutations within the GRN gene leads to progressive neuronal atrophy in the form of frontotemporal lobar degeneration (FTLD). This form of the disease is associated with neuronal inclusions that bear the ubiquitinated TAR DNA Binding Protein-43 (TDP-43) molecular signature (FTLD-U). The neurotrophic properties of PGRN in vitro have recently been reported but the role of PGRN in neurons is not well understood. Here we document the neuronal expression and functions of PGRN in spinal cord motoneuron (MN) maturation and branching in vivo using zebrafish, a well established model of vertebrate embryonic development.
Results
Whole-mount in situ hybridization and immunohistochemical analyses of zebrafish embryos revealed that zfPGRN-A is expressed within the peripheral and central nervous systems including the caudal primary (CaP) MNs within the spinal cord. Knockdown of zfPGRN-A mRNA translation mediated by antisense morpholino oligonucleotides disrupted normal CaP MN development resulting in both truncated MNs and inappropriate early branching. Ectopic over-expression of zfPGRN-A mRNA resulted in increased MN branching and rescued the truncation defects brought about by knockdown of zfPGRN-A expression. The ability of PGRN to interact with established MN developmental pathways was tested. PGRN over-expression was found to reverse the truncation defect resulting from knockdown of Survival of motor neuron 1 (smn1). This is involved in small ribonucleoprotein biogenesis RNA processing, mutations of which cause Spinal Muscular Atrophy (SMA) in humans. It did not reverse the MN defects caused by interfering with the neuronal guidance pathway by knockdown of expression of NRP-1, a semaphorin co-receptor.
Conclusions
Expression of PGRN within MNs and the observed phenotypes resulting from mRNA knockdown and over-expression are consistent with a role in the regulation of spinal cord MN development and branching. This study presents the first in vivo demonstration of the neurotrophic properties of PGRN and suggests possible future therapeutic applications in the treatment of neurodegenerative diseases.
doi:10.1186/1750-1326-5-41
PMCID: PMC2974670  PMID: 20946666
4.  Targeted manipulation of the sortilin–progranulin axis rescues progranulin haploinsufficiency 
Human Molecular Genetics  2013;23(6):1467-1478.
Progranulin (GRN) mutations causing haploinsufficiency are a major cause of frontotemporal lobar degeneration (FTLD-TDP). Recent discoveries demonstrating sortilin (SORT1) is a neuronal receptor for PGRN endocytosis and a determinant of plasma PGRN levels portend the development of enhancers targeting the SORT1–PGRN axis. We demonstrate the preclinical efficacy of several approaches through which impairing PGRN's interaction with SORT1 restores extracellular PGRN levels. Our report is the first to demonstrate the efficacy of enhancing PGRN levels in iPSC neurons derived from frontotemporal dementia (FTD) patients with PGRN deficiency. We validate a small molecule preferentially increases extracellular PGRN by reducing SORT1 levels in various mammalian cell lines and patient-derived iPSC neurons and lymphocytes. We further demonstrate that SORT1 antagonists and a small-molecule binder of PGRN588–593, residues critical for PGRN–SORT1 binding, inhibit SORT1-mediated PGRN endocytosis. Collectively, our data demonstrate that the SORT1–PGRN axis is a viable target for PGRN-based therapy, particularly in FTD-GRN patients.
doi:10.1093/hmg/ddt534
PMCID: PMC3929086  PMID: 24163244
5.  Traumatic Brain Injury May Increase the Risk for Frontotemporal Dementia through Reduced Progranulin 
Neuro-Degenerative Diseases  2010;6(5-6):219-220.
Frontotemporal lobar degeneration with TAR-DNA-binding protein inclusions (FTLD-TDP) is the most common pathological subtype of frontotemporal dementia (FTD). Mutations leading to a loss of function in the progranulin gene (PGRN) are the most common known cause of FTLD-TDP. In agreement with the proposed loss of function disease mechanism, several groups have reported decreased plasma levels of PGRN in patients carrying PGRN mutations compared to individuals without PGRN mutations. We propose that traumatic brain injury (TBI), an environmental factor, may also increase the risk of FTD by altering PGRN metabolism. TBI may lead to an increase in the central nervous system levels of microglial elastases, which proteolyze PGRN into proinflammatory products called granulins causing a reduction in PGRN levels. Hence, inhibiting microglial activation may have an important implication for the prevention of FTD in patients with TBI.
doi:10.1159/000258704
PMCID: PMC2837889  PMID: 20145419
Frontotemporal dementia; Progranulin; Traumatic brain injury; Microglia; Elastase
6.  Frontotemporal Dementia: Implications for Understanding Alzheimer Disease 
Frontotemporal dementia (FTD) comprises a group of behavioral, language, and movement disorders. On the basis of the nature of the characteristic protein inclusions, frontotemporal lobar degeneration (FTLD) can be subdivided into the common FTLD-tau and FTLD-TDP as well as the less common FTLD-FUS and FTLD-UPS. Approximately 10% of cases of FTD are inherited in an autosomal-dominant manner. Mutations in seven genes cause FTD, with those in tau (MAPT), chromosome 9 open reading frame 72 (C9ORF72), and progranulin (GRN) being the most common. Mutations in MAPT give rise to FTLD-tau and mutations in C9ORF72 and GRN to FTLD-TDP. The other four genes are transactive response–DNA binding protein-43 (TARDBP), fused in sarcoma (FUS), valosin-containing protein (VCP), and charged multivesicular body protein 2B (CHMP2B). Mutations in TARDBP and VCP give rise to FTLD-TDP, mutations in FUS to FTLD-FUS, and mutations in CHMP2B to FTLD-UPS. The discovery that mutations in MAPT cause neurodegeneration and dementia has important implications for understanding Alzheimer disease.
Mutations in the tau (MAPT) gene account for ∼5% of frontotemporal dementia cases. They give rise to characteristic protein inclusions, providing insight into tau pathology in Alzheimer disease.
doi:10.1101/cshperspect.a006254
PMCID: PMC3281593  PMID: 22355793
7.  Novel Progranulin Mutation Detected in 2 Patients With FTLD 
Frontotemporal lobar degeneration (FTLD) with ubiquitin-positive, tau-negative inclusions, and linkage to chromosome 17 was recently found to be caused by mutations in the progranulin (PGRN) gene. In this study, we screened a group of 51 FTLD patients for PGRN mutations and identified a novel exon 6 splice donor site deletion (IVS6+5_8delGTGA) in 2 unrelated patients. This mutation displayed an altered splicing pattern generating 2 aberrant transcripts and causing frameshifts of the coding sequence, premature termination codons, and a near absence of PGRN mRNA from the mutated alleles most likely through nonsense-mediated decay. The subsequent PGRN haploinsufficiency is consistent with previously described PGRN mutations. We present a molecular characterization of the IVS6+5_8delGTGA mutation and also describe clinical and neuropathologic features from the 2 patients carrying this PGRN mutation. From the screening of these 51 FTLD patients, we could also identify the earlier reported mutation Gln130fs, and several coding sequence variants that are most likely nonpathogenic.
doi:10.1097/WAD.0b013e3181fbc22c
PMCID: PMC3710288  PMID: 20975516
frontotemporal lobar degeneration; frontotemporal dementia; progranulin; ubiquitin; TDP-43
8.  TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions 
Acta neuropathologica  2014;127(3):407-418.
Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at TMEM106B influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA binding protein of 43kDa (FTLD-TDP). Previous reports have shown that TMEM106B is a genetic modifier of FTLD-TDP caused by progranulin (GRN) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with C9orf72 expansions (n=14), with the major allele correlated with later age at death (p=0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with C9orf72 expansions (n=75), again finding that the major allele associates with later age at death (p=0.016), as well as later age at onset (p=0.019). In contrast, TMEM106B genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for GRN mutations or C9orf72 expansions. Thus, TMEM106B is a genetic modifier of FTLD with C9orf72 expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in C9orf72 expansion carriers, providing an example of sign epistasis in human neurodegenerative disease.
doi:10.1007/s00401-013-1239-x
PMCID: PMC4003885  PMID: 24442578
TMEM106B; C9orf72; frontotemporal dementia; frontotemporal lobar degeneration; amyotrophic lateral sclerosis; genetic modifier
9.  Sortilin-Mediated Endocytosis Determines Levels of the Fronto-Temporal Dementia Protein, Progranulin 
Neuron  2010;68(4):654-667.
SUMMARY
The most common inherited form of Fronto-Temporal Lobar Degeneration (FTLD) known stems from Progranulin (GRN) mutation, and exhibits TDP-43 plus ubiquitin aggregates. Despite the causative role of GRN haploinsufficiency in FTLD-TDP, the neurobiology of this secreted glycoprotein is unclear. Here, we examined PGRN binding to the cell surface. PGRN binds to cortical neurons via its C-terminus, and unbiased expression cloning identifies Sortilin (Sort1) as a binding site. Sort1−/− neurons exhibit reduced PGRN binding. In the CNS, Sortilin is expressed by neurons and PGRN is most strongly expressed by activated microglial cells after injury. Sortilin rapidly endocytoses and delivers PGRN to lysosomes. Mice lacking Sortilin have elevations in brain and serum PGRN levels of 2.5- to 5-fold. The 50% PGRN decrease causative in FTLD-TDP cases is mimicked in GRN+/− mice, and is fully normalized by Sort1 ablation. Sortilin-mediated PGRN endocytosis is likely to play a central role in FTLD-TDP pathophysiology.
doi:10.1016/j.neuron.2010.09.034
PMCID: PMC2990962  PMID: 21092856
10.  Genetic and Clinical Features of Progranulin-Associated Frontotemporal Lobar Degeneration 
Archives of neurology  2011;68(4):488-497.
Objective
To assess the relative frequency of unique mutations and their associated characteristics in 97 individuals with mutations in progranulin (GRN), an important cause of frontotemporal lobar degeneration (FTLD).
Participants and Design
A 46-site International Frontotemporal Lobar Degeneration Collaboration was formed to collect cases of FTLD with TAR DNA-binding protein of 43-kDa (TDP-43)–positive inclusions (FTLD-TDP). We identified 97 individuals with FTLD-TDP with pathogenic GRN mutations (GRN+ FTLD-TDP), assessed their genetic and clinical characteristics, and compared them with 453 patients with FTLD-TDP in which GRN mutations were excluded (GRN− FTLD-TDP). No patients were known to be related. Neuropathologic characteristics were confirmed as FTLD-TDP in 79 of the 97 GRN+ FTLDTDP cases and all of the GRN− FTLD-TDP cases.
Results
Age at onset of FTLD was younger in patients with GRN+ FTLD-TDP vs GRN− FTLD-TDP (median, 58.0 vs 61.0 years; P<.001), as was age at death (median, 65.5 vs 69.0 years; P<.001). Concomitant motor neuron disease was much less common in GRN+ FTLDTDP vs GRN− FTLD-TDP (5.4% vs 26.3%; P<.001). Fifty different GRN mutations were observed, including 2 novel mutations: c.139delG (p.D47TfsX7) and c.378C>A (p.C126X). The 2 most common GRN mutations were c.1477C>T (p.R493X, found in 18 patients, representing 18.6% of GRN cases) and c.26C>A (p.A9D, found in 6 patients, representing 6.2% of cases). Patients with the c.1477C>T mutation shared a haplotype on chromosome 17; clinically, they resembled patients with other GRN mutations. Patients with the c.26C>A mutation appeared to have a younger age at onset of FTLD and at death and more parkinsonian features than those with other GRN mutations.
Conclusion
GRN+ FTLD-TDP differs in key features from GRN− FTLD-TDP.
doi:10.1001/archneurol.2011.53
PMCID: PMC3160280  PMID: 21482928
11.  Common Variant in GRN Is a Genetic Risk Factor for Hippocampal Sclerosis in the Elderly 
Neuro-Degenerative Diseases  2010;7(1-3):170-174.
Background
Hippocampal sclerosis (HpScl) is common in elderly subjects with dementia, either alone or accompanied by other pathologic processes. It is also found in >70% of frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions (FTLD-TDP). TDP-43 inclusions are detected in >20% of Alzheimer disease (AD) and >70% of HpScl cases. The most common cause of FTLD-TDP is mutation in the progranulin gene (GRN). Recently, a common genetic variant in the 3′ untranslated region (3′UTR) of GRN (rs5848; c.*78C>T) located in a microRNA binding site regulated progranulin expression, and the T-allele was increased in FTLD-TDP compared to controls.
Objective
The goal of this study was to determine if the 3′UTR variant in GRN was associated with TDP-43 immunoreactivity in AD with and without HpScl.
Methods
644 cases of pathologically confirmed AD, including 57 with HpScl, were screened for TDP-43 immunoreactivity and were genotyped at the GRN 3′UTR single-nucleotide polymorphism rs5848 using previously published methods.
Results
There was a trend (p = 0.06) for TDP-43 immunoreactivity, but a very significant (p = 0.005) association of HpScl with the variant, with 72% of AD with HpScl carrying a T-allele, compared to 51% of AD without HpScl carrying a T-allele.
Conclusion
The results suggest that a genetic variant in GRN leading to decreased levels of progranulin may be a risk factor for HpScl in AD, while its role in TDP-43 immunoreactivity in AD remains less certain.
doi:10.1159/000289231
PMCID: PMC2859236  PMID: 20197700
Alzheimer's disease; Hippocampal sclerosis; Immunohistochemistry; Progranulin gene
12.  Expression of TMEM106B, the frontotemporal lobar degeneration-associated protein, in normal and diseased human brain 
Background
Frontotemporal lobar degeneration (FTLD) is the second most common cause of dementia in individuals under 65 years old and manifests as alterations in behavior, personality, or language secondary to degeneration of the frontal and/or temporal lobes. FTLD-TDP, the largest neuropathological subset of FTLD, is characterized by hyperphosphorylated, ubiquitinated TAR DNA-binding protein 43 (TDP-43) inclusions. Mutations in progranulin (GRN), a neuroprotective growth factor, are one of the most common Mendelian genetic causes of FTLD-TDP. Moreover, a recent genome-wide association study (GWAS) identified multiple SNPs within the uncharacterized gene TMEM106B that significantly associated with FTLD-TDP, suggesting that TMEM106B genotype confers risk for FTLD-TDP. Indeed, TMEM106B expression levels, which correlate with TMEM106B genotype, may play a role in the pathogenesis of disease.
Results
Since little is known about TMEM106B and its expression in human brain, we performed immunohistochemical studies of TMEM106B in postmortem human brain samples from normal individuals, FTLD-TDP individuals with and without GRN mutations, and individuals with other neurodegenerative diseases. We find that TMEM106B protein is cytoplasmically expressed in both histopathologically affected and unaffected areas of the brain by neurons, glia, and endothelial cells/pericytes. Furthermore, we demonstrate that TMEM106B expression may differ among neuronal subtypes. Finally, we show that TMEM106B neuronal expression is significantly more disorganized in FTLD-TDP cases with GRN mutations, compared to normal and disease controls, including FTLD-TDP cases without GRN mutations.
Conclusions
Our data provide an initial neuropathological characterization of the newly discovered FTLD-TDP-associated protein TMEM106B. In addition, we demonstrate that FTLD-TDP cases with GRN mutations exhibit a loss of neuronal TMEM106B subcellular localization, adding to evidence that TMEM106B and progranulin may be pathophysiologically linked in FTLD-TDP.
doi:10.1186/2051-5960-1-36
PMCID: PMC3893524  PMID: 24252750
TMEM106B; Frontotemporal lobar degeneration; Frontotemporal dementia; TDP-43; Progranulin; FTLD-TDP
13.  Progranulin functions as a neurotrophic factor to regulate neurite outgrowth and enhance neuronal survival 
The Journal of Cell Biology  2008;181(1):37-41.
Recently, mutations in the progranulin (PGRN) gene were found to cause familial and apparently sporadic frontotemporal lobe dementia (FTLD). Moreover, missense changes in PGRN were identified in patients with motor neuron degeneration, a condition that is related to FTLD. Most mutations identified in patients with FTLD until now have been null mutations. However, it remains unknown whether PGRN protein levels are reduced in the central nervous system from such patients. The effects of PGRN on neurons also remain to be established. We report that PGRN levels are reduced in the cerebrospinal fluid from FTLD patients carrying a PGRN mutation. We observe that PGRN and GRN E (one of the proteolytic fragments of PGRN) promote neuronal survival and enhance neurite outgrowth in cultured neurons. These results demonstrate that PGRN/GRN is a neurotrophic factor with activities that may be involved in the development of the nervous system and in neurodegeneration.
doi:10.1083/jcb.200712039
PMCID: PMC2287280  PMID: 18378771
14.  TMEM106B, the risk gene for frontotemporal dementia, is regulated by the miRNA-132/212 cluster and affects progranulin pathways 
Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) is a fatal neurodegenerative disease with no available treatments. Mutations in the progranulin gene (GRN) causing impaired production or secretion of progranulin are a common Mendelian cause of FTLD-TDP; additionally, common variants at chromosome 7p21 in the uncharacterized gene TMEM106B were recently linked by genome-wide association to FTLD-TDP with and without GRN mutations. Here we show that TMEM106B is neuronally expressed in postmortem human brain tissue, and that expression levels are increased in FTLD-TDP brain. Furthermore, using an unbiased, microarray-based screen of over 800 microRNAs, we identify microRNA-132 as the top microRNA differentiating FTLD-TDP and control brains, with <50% normal expression levels of three members of the microRNA-132 cluster (microRNA-132, microRNA-132*, and microRNA-212) in disease. Computational analyses, corroborated empirically, demonstrate that the top mRNA target of both microRNA-132 and microRNA-212 is TMEM106B; both microRNAs repress TMEM106B expression through shared microRNA-132/212 binding sites in the TMEM106B 3’UTR. Increasing TMEM106B expression to model disease results in enlargement and poor acidification of endo-lysosomes, as well as impairment of mannose-6-phosphate-receptor trafficking. Finally, endogenous neuronal TMEM106B co-localizes with progranulin in late endo-lysosomes, and TMEM106B over-expression increases intracellular levels of progranulin. Thus, TMEM106B is an FTLD-TDP risk gene, with microRNA-132/212 depression as an event which can lead to aberrant over-expression of TMEM106B, which in turn alters progranulin pathways. Evidence for this pathogenic cascade includes the striking convergence of two independent, genomic-scale screens on a microRNA:mRNA regulatory pair. Our findings open novel directions for elucidating miRNA-based therapies in FTLD-TDP.
doi:10.1523/JNEUROSCI.0521-12.2012
PMCID: PMC3446826  PMID: 22895706
Frontotemporal dementia; microRNA-132; microRNA-212; progranulin; TDP-43; frontotemporal lobar degeneration; TMEM106B
15.  Progranulin in frontotemporal lobar degeneration and neuroinflammation 
Progranulin (PGRN) is a pleiotropic protein that has gained the attention of the neuroscience community with recent discoveries of mutations in the gene for PGRN that cause frontotemporal lobar degeneration (FTLD). Pathogenic mutations in PGRN result in null alleles, and the disease is likely the result of haploinsufficiency. Little is known about the normal function of PGRN in the central nervous system apart from a role in brain development. It is expressed by microglia and neurons. In the periphery, PGRN is involved in wound repair and inflammation. High PGRN expression has been associated with more aggressive growth of various tumors. The properties of full length PGRN are distinct from those of proteolytically derived peptides, referred to as granulins (GRNs). While PGRN has trophic properties, GRNs are more akin to inflammatory mediators such as cytokines. Loss of the neurotrophic properties of PGRN may play a role in selective neuronal degeneration in FTLD, but neuroinflammation may also be important. Gene expression studies suggest that PGRN is up-regulated in a variety of neuroinflammatory conditions, and increased PGRN expression by microglia may play a pivotal role in the response to brain injury, neuroinflammation and neurodegeneration.
doi:10.1186/1742-2094-4-7
PMCID: PMC1805428  PMID: 17291356
16.  Brain progranulin expression in GRN-associated frontotemporal lobar degeneration 
Acta neuropathologica  2009;119(1):111-122.
Frontotemporal lobar degeneration with TDP- 43 inclusions (FTLD-TDP) is characterized by progressive decline in behavior, executive function, and language. Progranulin (GRN) gene mutations are pathogenic for FTLD-TDP, and GRN transcript haploinsufficiency is the proposed disease mechanism. However, the evidence for this hypothesis comes mainly from blood-derived cells; we measured progranulin expression in brain. We characterized mRNA and protein levels of progranulin from four brain regions (frontal cortex, temporal cortex, occipital cortex, and cerebellum) in FTLD-TDP patients with and without GRN mutations, as well as neurologically normal individuals. Moreover, we performed immunohistochemistry to evaluate the degree of TDP-43 pathology and microglial infiltration present in these groups. In most brain regions, patients with GRN mutations showed mRNA levels comparable to normal controls and to FTLD-TDP without GRN mutations. However, GRN transcript levels in a brain region severely affected by disease (frontal cortex) were increased in mutation-bearing patients. When compared with normal individuals, GRN mutation-bearing cases had a significant reduction in the amount of progranulin protein in the cerebellum and occipital cortex, but not in the frontal and temporal cortices. In GRN mutant cases, GRN mRNA originated from the normal allele, and moderate microglial infiltration was observed. In conclusion, GRN mutation carriers have increased levels of mRNA transcript from the normal allele in brain, and proliferation of microglia likely increases progranulin levels in affected regions of the FTLD-TDP brain, and whether or not these findings underlie the accumulation of TDP-43 pathology in FTLD-TDP linked to GRN mutations remains to be determined.
doi:10.1007/s00401-009-0576-2
PMCID: PMC3104467  PMID: 19649643
Progranulin; TDP-43; Frontotemporal dementia; Frontotemporal lobar degeneration; Microglia
17.  Potential Mechanisms of Progranulin-deficient FTLD 
Frontotemporal lobar dementia (FTLD) is the most common cause of dementia in patients younger than 60 years of age, and causes progressive neurodegeneration of the frontal and temporal lobes usually accompanied by devastating changes in language or behavior in affected individuals. Mutations in the progranulin (GRN) gene account for a significant fraction of familial FTLD, and in the vast majority of cases, these mutations lead to reduced expression of progranulin via nonsense-mediated mRNA decay. Progranulin is a secreted glycoprotein that regulates a diverse range of cellular functions including cell proliferation, cell migration, and inflammation. Recent fundamental discoveries about progranulin biology, including the findings that sortilin and tumor necrosis factor receptor (TNFR) are high affinity progranulin receptors, are beginning to shed light on the mechanism(s) by which progranulin deficiency causes FTLD. This review will explore how alterations in basic cellular functions due to PGRN deficiency, both intrinsic and extrinsic to neurons, might lead to the development of FTLD.
doi:10.1007/s12031-011-9622-3
PMCID: PMC3767571  PMID: 21892758
Progranulin; Frontotemporal lobar dementia; Sortilin; Tumor necrosis factor receptor; TDP-43; Neuroinflammation
18.  Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions 
Van Deerlin, Vivianna M. | Sleiman, Patrick M. A. | Martinez-Lage, Maria | Chen-Plotkin, Alice | Wang, Li-San | Graff-Radford, Neill R | Dickson, Dennis W. | Rademakers, Rosa | Boeve, Bradley F. | Grossman, Murray | Arnold, Steven E. | Mann, David M.A. | Pickering-Brown, Stuart M. | Seelaar, Harro | Heutink, Peter | van Swieten, John C. | Murrell, Jill R. | Ghetti, Bernardino | Spina, Salvatore | Grafman, Jordan | Hodges, John | Spillantini, Maria Grazia | Gilman, Sid' | Lieberman, Andrew P. | Kaye, Jeffrey A. | Woltjer, Randall L. | Bigio, Eileen H | Mesulam, Marsel | al-Sarraj, Safa | Troakes, Claire | Rosenberg, Roger N. | White, Charles L. | Ferrer, Isidro | Lladó, Albert | Neumann, Manuela | Kretzschmar, Hans A. | Hulette, Christine Marie | Welsh-Bohmer, Kathleen A. | Miller, Bruce L | Alzualde, Ainhoa | de Munain, Adolfo Lopez | McKee, Ann C. | Gearing, Marla | Levey, Allan I. | Lah, James J. | Hardy, John | Rohrer, Jonathan D. | Lashley, Tammaryn | Mackenzie, Ian R.A. | Feldman, Howard H. | Hamilton, Ronald L. | Dekosky, Steven T. | van der Zee, Julie | Kumar-Singh, Samir | Van Broeckhoven, Christine | Mayeux, Richard | Vonsattel, Jean Paul G. | Troncoso, Juan C. | Kril, Jillian J | Kwok, John B.J. | Halliday, Glenda M. | Bird, Thomas D. | Ince, Paul G. | Shaw, Pamela J. | Cairns, Nigel J. | Morris, John C. | McLean, Catriona Ann | DeCarli, Charles | Ellis, William G. | Freeman, Stefanie H. | Frosch, Matthew P. | Growdon, John H. | Perl, Daniel P. | Sano, Mary | Bennett, David A. | Schneider, Julie A. | Beach, Thomas G. | Reiman, Eric M. | Woodruff, Bryan K. | Cummings, Jeffrey | Vinters, Harry V. | Miller, Carol A. | Chui, Helena C. | Alafuzoff, Irina | Hartikainen, Päivi | Seilhean, Danielle | Galasko, Douglas | Masliah, Eliezer | Cotman, Carl W. | Tuñón, M. Teresa | Martínez, M. Cristina Caballero | Munoz, David G. | Carroll, Steven L. | Marson, Daniel | Riederer, Peter F. | Bogdanovic, Nenad | Schellenberg, Gerard D. | Hakonarson, Hakon | Trojanowski, John Q. | Lee, Virginia M.-Y.
Nature genetics  2010;42(3):234-239.
Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA binding protein (TDP-43) inclusions (FTLD-TDP)1. FTLD-TDP is frequently familial resulting from progranulin (GRN) mutations. We assembled an international collaboration to identify susceptibility loci for FTLD-TDP, using genome-wide association (GWA). We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium (LD) block on 7p21 that contains TMEM106B in a GWA study (GWAS) on 515 FTLD-TDP cases. Three SNPs retained genome-wide significance following Bonferroni correction; top SNP rs1990622 (P=1.08×10−11; odds ratio (OR) minor allele (C) 0.61, 95% CI 0.53-0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P=2×10−4). TMEM106B variants may confer risk by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in patients with GRN mutations. Our data implicate TMEM106B as a strong risk factor for FTLD-TDP suggesting an underlying pathogenic mechanism.
doi:10.1038/ng.536
PMCID: PMC2828525  PMID: 20154673
19.  Genetics of frontotemporal lobar degeneration 
Annals of Indian Academy of Neurology  2010;13(Suppl2):S55-S62.
Frontotemporal lobar degeneration (FTLD) is a highly heterogenous group of progressive neurodegenerative disorders characterized by atrophy of prefrontal and anterior temporal cortices. Recently, the research in the field of FTLD has gained increased attention due to the clinical, neuropathological, and genetic heterogeneity and has increased our understanding of the disease pathogenesis. FTLD is a genetically complex disorder. It has a strong genetic basis and 50% of patients show a positive family history for FTLD. Linkage studies have revealed seven chromosomal loci and a number of genes including MAPT, PGRN, VCP, and CHMB-2B are associated with the disease. Neuropathologically, FTLD is classified into tauopathies and ubiquitinopathies. The vast majority of FTLD cases are characterized by pathological accumulation of tau or TDP-43 positive inclusions, each as an outcome of mutations in MAPT or PGRN, respectively. Identification of novel proteins involved in the pathophysiology of the disease, such as progranulin and TDP-43, may prove to be excellent biomarkers of disease progression and thereby lead to the development of better therapeutic options through pharmacogenomics. However, much more dissections into the causative pathways are needed to get a full picture of the etiology. Over the past decade, advances in research on the genetics of FTLD have revealed many pathogenic mutations leading to different clinical manifestations of the disease. This review discusses the current concepts and recent advances in our understanding of the genetics of FTLD.
doi:10.4103/0972-2327.74246
PMCID: PMC3039162  PMID: 21369419
Frontotemporal lobar degeneration; genetic risk factors; microtubule-associated protein tau; mutations; progranulin; TDP-43
20.  rs5848 Polymorphism and Serum Progranulin Level 
Objective
To assess the influence of rs5848 polymorphism in serum progranulin (PGRN) level in a cohort of subjects with Alzheimer and related dementias from a tertiary referral clinic.
Background
Mutations in the GRN gene cause autosomal dominant frontotemporal dementia (FTD) with TDP-43 pathology (FTLD-TDP) through haploinsufficiency. It has recently been shown that homozygous carriers of the T-allele of rs5848 have an elevated risk developing FTD, and this polymorphism may play a role in the pathogenesis of other dementia by modifying progranulin level. We hypothesize that genotype of rs5848 may influence serum PGRN level in AD, FTD, and other dementias.
Methods
Blood samples were obtained from patients with cognitive impairment and dementia referred to a tertiary dementia clinic, as well as samples from a cohort of healthy controls. Serum PGRN level was measured using an ELISA assay, and rs5848 genotype was determined by a TaqMan assay.
Results
We found that rs5848 SNP significantly influenced serum PGRN level, with TT genotype having the lowest levels, CC the highest. This relationship is observed in each of the subgroups. We also confirmed that GRN mutation carriers had significantly lower serum PGRN levels than all other groups.
Conclusions
The rs5848 polymorphism significantly influences serum PGRN with TT carriers having a lower level of serum PGRN then CT and CC carriers. This is consistent with the finding that miR-659 binding to the high risk T allele of rs5848 may augment translational inhibition of GRN and alter risk of FTD and possibly other dementias.
doi:10.1016/j.jns.2010.10.009
PMCID: PMC3085023  PMID: 21047645
Frontotemporal Dementia; Progranulin; PGRN; GRN; rs5848; genetic polymorphism; biomarker
21.  Progranulin regulates neuronal outgrowth independent of Sortilin 
Background
Progranulin (PGRN), a widely secreted growth factor, is involved in multiple biological functions, and mutations located within the PGRN gene (GRN) are a major cause of frontotemporal lobar degeneration with TDP-43-positive inclusions (FLTD-TDP). In light of recent reports suggesting PGRN functions as a protective neurotrophic factor and that sortilin (SORT1) is a neuronal receptor for PGRN, we used a Sort1-deficient (Sort1−/−) murine primary hippocampal neuron model to investigate whether PGRN’s neurotrophic effects are dependent on SORT1. We sought to elucidate this relationship to determine what role SORT1, as a regulator of PGRN levels, plays in modulating PGRN’s neurotrophic effects.
Results
As the first group to evaluate the effect of PGRN loss in Grn knockout primary neuronal cultures, we show neurite outgrowth and branching are significantly decreased in Grn−/− neurons compared to wild-type (WT) neurons. More importantly, we also demonstrate that PGRN overexpression can rescue this phenotype. However, the recovery in outgrowth is not observed following treatment with recombinant PGRN harboring missense mutations p.C139R, p.P248L or p.R432C, indicating that these mutations adversely affect the neurotrophic properties of PGRN. In addition, we also present evidence that cleavage of full-length PGRN into granulin peptides is required for increased neuronal outgrowth, suggesting that the neurotrophic functions of PGRN are contained within certain granulins. To further characterize the mechanism by which PGRN impacts neuronal morphology, we assessed the involvement of SORT1. We demonstrate that PGRN induced-outgrowth occurs in the absence of SORT1 in Sort1−/− cultures.
Conclusion
We demonstrate that loss of PGRN impairs proper neurite outgrowth and branching, and that exogenous PGRN alleviates this impairment. Furthermore, we determined that exogenous PGRN induces outgrowth independent of SORT1, suggesting another receptor(s) is involved in PGRN induced neuronal outgrowth.
doi:10.1186/1750-1326-7-33
PMCID: PMC3508877  PMID: 22781549
Progranulin; Sortilin; Neuronal outgrowth; Frontotemporal lobar degeneration; Neurotrophic factor
22.  Neuropathological heterogeneity in frontotemporal lobar degeneration with TDP-43 proteinopathy: a quantitative study of 94 cases using principal components analysis 
Journal of Neural Transmission  2009;117(2):227-239.
Studies suggest that frontotemporal lobar degeneration with transactive response DNA-binding protein of 43 kDa (TDP-43) proteinopathy (FTLD-TDP) is heterogeneous with division into four or five subtypes. To determine the degree of heterogeneity and the validity of the subtypes, we studied neuropathological variation within the frontal and temporal lobes of 94 cases of FTLD-TDP using quantitative estimates of density and principal components analysis (PCA). A PCA based on the density of TDP-43 immunoreactive neuronal cytoplasmic inclusions, oligodendroglial inclusions, neuronal intranuclear inclusions, and dystrophic neurites, surviving neurons, enlarged neurons, and vacuolation suggested that cases were not segregated into distinct subtypes. Variation in the density of the vacuoles was the greatest source of variation between cases. A PCA based on TDP-43 pathology alone suggested that cases of FTLD-TDP with progranulin (GRN) mutation segregated to some degree. The pathological phenotype of all four subtypes overlapped but subtypes 1 and 4 were the most distinctive. Cases with coexisting motor neuron disease (MND) or hippocampal sclerosis (HS) also appeared to segregate to some extent. We suggest: (1) pathological variation in FTLD-TDP is best described as a ‘continuum’ without clearly distinct subtypes, (2) vacuolation was the single greatest source of variation and reflects the ‘stage’ of the disease, and (3) within the FTLD-TDP ‘continuum’ cases with GRN mutation and with coexisting MND or HS may have a more distinctive pathology.
doi:10.1007/s00702-009-0350-6
PMCID: PMC2830004  PMID: 20012109
Frontotemporal lobar degeneration with TDP-43 proteinopathy; FTLD with ubiquitin-positive inclusions; TAR DNA-binding protein of 43 kDa; Neuronal cytoplasmic inclusions; Neuropathologic heterogeneity; Principal components analysis
23.  Sporadic Corticobasal Syndrome due to FTLD-TDP 
Acta neuropathologica  2009;119(3):365-374.
Sporadic corticobasal syndrome (CBS) has been associated with diverse pathological substrates, but frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions (FTLD-TDP) has only been linked to CBS among progranulin mutation carriers. We report the clinical, neuropsychological, imaging, genetic, and neuropathological features of GS, a patient with sporadic corticobasal syndrome. Genetic testing revealed no mutations in the microtubule associated protein tau (MAPT) or progranulin (PGRN) genes, but GS proved homozygous for the T allele of the rs5848 PGRN variant. Autopsy showed ubiquitin and TDP-43 pathology most similar to a pattern previously associated with PGRN mutation carriers. These findings confirm that FTLD-TDP should be included in the pathological differential diagnosis for sporadic CBS.
doi:10.1007/s00401-009-0605-1
PMCID: PMC2832091  PMID: 19876635
corticobasal degeneration; TDP-43; frontotemporal lobar degeneration; progranulin
24.  Circulating progranulin as a biomarker for neurodegenerative diseases 
Progranulin is a growth factor involved in the regulation of multiple processes including tumorigenesis, wound repair, development, and inflammation. The recent discovery that mutations in the gene encoding for progranulin (GRN) cause frontotemporal lobar degeneration (FTLD), and other neurodegenerative diseases leading to dementia, has brought renewed interest in progranulin and its functions in the central nervous system. GRN null mutations cause protein haploinsufficiency, leading to a significant decrease in progranulin levels that can be detected in plasma, serum and cerebrospinal fluid (CSF) of mutation carriers. The dosage of circulating progranulin sped up the identification of GRN mutations thus favoring genotype-phenotype correlation studies. Researchers demonstrated that, in GRN null mutation carriers, the shortage of progranulin invariably precedes clinical symptoms and thus mutation carriers are “captured” regardless of their disease status. GRN is a particularly appealing gene for drug targeting, in the way that boosting its expression may be beneficial for mutation carriers, preventing or delaying the onset of GRN-related neurodegenerative diseases. Physiological regulation of progranulin expression level is only partially known. Progranulin expression reflects mutation status and, intriguingly, its levels can be modulated by some additional factor (i.e. genetic background; drugs). Thus, factors increasing the production and secretion of progranulin from the normal gene are promising potential therapeutic avenues. In conclusion, peripheral progranulin is a nonintrusive highly accurate biomarker for early identification of mutation carriers and for monitoring future treatments that might boost the level of this protein.
PMCID: PMC3560461  PMID: 23383391
Progranulin; haploinsufficiency; cut-off; blood; CSF; expression; frontotemporal; dementia; GRN; modulator
25.  ALS and FTLD: two faces of TDP-43 proteinopathy 
European Journal of Neurology  2008;15(8):772-780.
Major discoveries have been made in the recent past in the genetics, biochemistry and neuropathology of frontotemporal lobar degeneration (FTLD). TAR DNA-binding protein 43 (TDP-43), encoded by the TARDBP gene, has been identified as the major pathological protein of FTLD with ubiquitin-immunoreactive (ub-ir) inclusions (FTLD-U) with or without amyotrophic lateral sclerosis (ALS) and sporadic ALS. Recently, mutations in the TARDBP gene in familial and sporadic ALS have been reported which demonstrate that abnormal TDP-43 alone is sufficient to cause neurodegeneration. Several familial cases of FTLD-U, however, are now known to have mutations in the progranulin (GRN) gene, but granulin is not a component of the TDP-43- and ub-ir inclusions. Further, TDP-43 is found to be a component of the inclusions of an increasing number of neurodegenerative diseases. Other FTLD-U entities with TDP-43 proteinopathy include: FTLD-U with valosin-containing protein (VCP) gene mutation and FTLD with ALS linked to chromosome 9p. In contrast, chromosome 3-linked dementia, FTLD-U with chromatin modifying protein 2B (CHMP2B) mutation, has ub-ir, TDP-43-negative inclusions. In summary, recent discoveries have generated new insights into the pathogenesis of a spectrum of disorders called TDP-43 proteinopathies including: FTLD-U, FTLD-U with ALS, ALS, and a broadening spectrum of other disorders. It is anticipated that these discoveries and a revised nosology of FTLD will contribute toward an accurate diagnosis, and facilitate the development of new diagnostic tests and therapeutics.
doi:10.1111/j.1468-1331.2008.02195.x
PMCID: PMC2801606  PMID: 18684309
amyotrophic lateral sclerosis; frontotemporal dementia; frontotemporal lobar degeneration; granulin; motor neuron disease; TARDBP; TDP-43; ubiquitin; valosin-containing protein

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