Background and Objective: Reduced progranulin levels are a hallmark of frontotemporal dementia (FTD) caused by loss-of-function (LoF) mutations in the progranulin gene (GRN). However, alterations of central nervous progranulin expression also occur in neurodegenerative disorders unrelated to GRN mutations, such as Alzheimer's disease. We hypothesised that central nervous progranulin levels are also reduced in GRN-negative FTD. Methods: Progranulin levels were determined in both cerebrospinal fluid (CSF) and serum in 75 subjects (37 FTD patients and 38 controls). All FTD patients were assessed by whole-exome sequencing for GRN mutations, yielding a target cohort of 34 patients without pathogenic mutations in GRN (GRN-negative cohort) and 3 GRN mutation carriers (2 LoF variants and 1 novel missense variant). Results: Not only the GRN mutation carriers but also the GRN-negative patients showed decreased CSF levels of progranulin (serum levels in GRN-negative patients were normal). The decreased CSF progranulin levels were unrelated to patients' increased CSF levels of total tau, possibly indicating different destructive neuronal processes within FTD neurodegeneration. The patient with the novel GRN missense variant (c.1117C>T, p.P373S) showed substantially decreased CSF levels of progranulin, comparable to the 2 patients with GRN LoF mutations, suggesting a pathogenic effect of this missense variant. Conclusions: Our results indicate that central nervous progranulin reduction is not restricted to the relatively rare cases of FTD caused by GRN LoF mutations, but also contributes to the more common GRN- negative forms of FTD. Central nervous progranulin reduction might reflect a partially distinct pathogenic mechanism underlying FTD neurodegeneration and is not directly linked to tau alterations.

Keywords:
Cerebrospinal fluid, Frontotemporal dementia, Neurodegeneration, Progranulin, Serum levels, Tau, Whole-exome sequencing
1.
Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C, et al: Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 2006;442:916-919.
2.
Cruts M, Gijselinck I, van der Zee J, Engelborghs S, Wils H, Pirici D, et al: Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 2006;442:920-924.
3.
Finch N, Baker M, Crook R, Swanson K, Kuntz K, Surtees R, et al: Plasma progranulin levels predict progranulin mutation status in frontotemporal dementia patients and asymptomatic family members. Brain 2009;132:583-591.
4.
Ghidoni R, Benussi L, Glionna M, Franzoni M, Binetti G: Low plasma progranulin levels predict progranulin mutations in frontotemporal lobar degeneration. Neurology 2008;71:1235-1239.
5.
Petkau TL, Leavitt BR: Progranulin in neurodegenerative disease. Trends Neurosci 2014;37:388-398.
6.
D'Alton S, Lewis J: Understanding the role of progranulin in Alzheimer's disease. Nat Med 2014;20:1099-1100.
7.
Minami SS, Min SW, Krabbe G, Wang C, Zhou Y, Asgarov R, et al: Progranulin protects against amyloid beta deposition and toxicity in Alzheimer's disease mouse models. Nat Med 2014;20:1157-1164.
8.
Wilke C, Gillardon F, Deuschle C, Dubois E, Hobert MA, Vom Hagen JM, et al: Serum levels of progranulin do not reflect cerebrospinal fluid levels in neurodegenerative disease. Curr Alzheimer Res 2016;13:654-662.
9.
Gorno-Tempini ML, Hillis AE, Weintraub S, Kertesz A, Mendez M, Cappa SF, et al: Classification of primary progressive aphasia and its variants. Neurology 2011;76:1006-1014.
10.
Rascovsky K, Hodges JR, Knopman D, Mendez MF, Kramer JH, Neuhaus J, et al: Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 2011;134:2456-2477.
11.
Palmqvist S, Zetterberg H, Blennow K, Vestberg S, Andreasson U, Brooks DJ, et al: Accuracy of brain amyloid detection in clinical practice using cerebrospinal fluid beta-amyloid 42: a cross-validation study against amyloid positron emission tomography. JAMA Neurol 2014;71:1282-1289.
12.
Youn BS, Bang SI, Kloting N, Park JW, Lee N, Oh JE, et al: Serum progranulin concentrations may be associated with macrophage infiltration into omental adipose tissue. Diabetes 2009;58:627-636.
13.
Le Bastard N, Coart E, Vanderstichele H, Vanmechelen E, Martin JJ, Engelborghs S: Comparison of two analytical platforms for the clinical qualification of Alzheimer's disease biomarkers in pathologically-confirmed dementia. J Alzheimers Dis 2013;33:117-131.
14.
Grossman M, Elman L, McCluskey L, McMillan CT, Boller A, Powers J, et al: Phosphorylated tau as a candidate biomarker for amyotrophic lateral sclerosis. JAMA Neurol 2014;71:442-448.
15.
Wilke C, Deuschle C, Rattay TW, Maetzler W, Synofzik M: Total tau is increased, but phosphorylated tau not decreased, in cerebrospinal fluid in amyotrophic lateral sclerosis. Neurobiol Aging 2015;36:1072-1074.
16.
1000 Genomes Project, Abecasis GR, Auton A, Brooks LD, DePristo MA, Durbin RM, et al: An integrated map of genetic variation from 1,092 human genomes. Nature 2012;491:56-65.
17.
EVS (Exome Variant Server): http://evsgswashingtonedu/EVS (2015).
18.
ExAC (Exome Aggregation Consortium): http://exacbroadinstituteorg (2015).
19.
Kumar P, Henikoff S, Ng PC: Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 2009;4:1073-1081.
20.
Pollard KS, Hubisz MJ, Rosenbloom KR, Siepel A: Detection of nonneutral substitution rates on mammalian phylogenies. Genome Res 2010;20:110-121.
21.
Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al: A method and server for predicting damaging missense mutations. Nat Methods 2010;7:248-249.
22.
Schwarz JM, Rodelsperger C, Schuelke M, Seelow D: MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods 2010;7:575-576.
23.
Chun S, Fay JC: Identification of deleterious mutations within three human genomes. Genome Res 2009;19:1553-1561.
24.
Nicholson AM, Finch NA, Thomas CS, Wojtas A, Rutherford NJ, Mielke MM, et al: Progranulin protein levels are differently regulated in plasma and CSF. Neurology 2014;82:1871-1878.
25.
Philips T, De Muynck L, Thu HN, Weynants B, Vanacker P, Dhondt J, et al: Microglial upregulation of progranulin as a marker of motor neuron degeneration. J Neuropathol Exp Neurol 2010;69:1191-1200.
26.
Ghidoni R, Stoppani E, Rossi G, Piccoli E, Albertini V, Paterlini A, et al: Optimal plasma progranulin cutoff value for predicting null progranulin mutations in neurodegenerative diseases: a multicenter Italian study. Neurodegener Dis 2012;9:121-127.
27.
Gibbons L, Rollinson S, Thompson JC, Robinson A, Davidson YS, Richardson A, et al: Plasma levels of progranulin and interleukin-6 in frontotemporal lobar degeneration. Neurobiol Aging 2015;36:1603 e1-4.
28.
Van Damme P, Van Hoecke A, Lambrechts D, Vanacker P, Bogaert E, Van Swieten J, et al: Progranulin functions as a neurotrophic factor to regulate neurite outgrowth and enhance neuronal survival. J Cell Biol 2008;181:37-41.
29.
Fenoglio C, Galimberti D, Cortini F, Kauwe JS, Cruchaga C, Venturelli E, et al: Rs5848 variant influences GRN mRNA levels in brain and peripheral mononuclear cells in patients with Alzheimer's disease. J Alzheimers Dis 2009;18:603-612.
30.
Kim HJ, Seong MW, Yun JY, Park SS, Lee JY, Jeon BS: Predicted pathogenic missense mutation of PGRN found in a normal control. Ann Neurol 2010;67:415-416.
31.
Shankaran SS, Capell A, Hruscha AT, Fellerer K, Neumann M, Schmid B, et al: Missense mutations in the progranulin gene linked to frontotemporal lobar degeneration with ubiquitin-immunoreactive inclusions reduce progranulin production and secretion. J Biol Chem 2008;283:1744-1753.
32.
Sleegers K, Brouwers N, Van Broeckhoven C: Reply. Ann Neurol 2010;68:119.
33.
Sleegers K, Brouwers N, Van Damme P, Engelborghs S, Gijselinck I, van der Zee J, et al: Serum biomarker for progranulin-associated frontotemporal lobar degeneration. Ann Neurol 2009;65:603-609.
34.
Borroni B, Benussi A, Archetti S, Galimberti D, Parnetti L, Nacmias B, et al: Csf p-tau/tau ratio as biomarker for TDP pathology in frontotemporal dementia. Amyotroph Lateral Scler Frontotemporal Degener 2014:1-6.
35.
Ballatore C, Lee VM, Trojanowski JQ: Tau-mediated neurodegeneration in Alzheimer's disease and related disorders. Nat Rev Neurosci 2007;8:663-672.
36.
Ishiguro K, Ohno H, Arai H, Yamaguchi H, Urakami K, Park JM, et al: Phosphorylated tau in human cerebrospinal fluid is a diagnostic marker for Alzheimer's disease. Neurosci Lett 1999;270:91-94.
37.
Noble W, Hanger DP, Miller CC, Lovestone S: The importance of tau phosphorylation for neurodegenerative diseases. Front Neurol 2013;4:83.
38.
Feneberg E, Steinacker P, Volk AE, Weishaupt JH, Wollmer MA, Boxer A, et al: Progranulin as a candidate biomarker for therapeutic trial in patients with ALS and FTLD. J Neural Transm (Vienna) 2016;123:289-296.
39.
Morenas-Rodriguez E, Cervera-Carles L, Vilaplana E, Alcolea D, Carmona-Iragui M, Dols-Icardo O, et al: Progranulin protein levels in cerebrospinal fluid in primary neurodegenerative dementias. J Alzheimers Dis 2015;50:539-546.
40.
De Muynck L, Van Damme P: Cellular effects of progranulin in health and disease. J Mol Neurosci 2011;45:549-560.
41.
Nguyen AD, Nguyen TA, Martens LH, Mitic LL, Farese RV Jr: Progranulin: at the interface of neurodegenerative and metabolic diseases. Trends Endocrinol Metab 2013;24:597-606.
42.
Capell A, Liebscher S, Fellerer K, Brouwers N, Willem M, Lammich S, et al: Rescue of progranulin deficiency associated with frontotemporal lobar degeneration by alkalizing reagents and inhibition of vacuolar ATPase. J Neurosci 2011;31:1885-1894.
43.
Cenik B, Sephton CF, Dewey CM, Xian X, Wei S, Yu K, et al: Suberoylanilide hydroxamic acid (vorinostat) up-regulates progranulin transcription: rational therapeutic approach to frontotemporal dementia. J Biol Chem 2011;286:16101-16108.
© 2016 S. Karger AG, Basel
2016
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.