Journal Article

DZNE-2020-05402

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Cerebrospinal Fluid Progranulin, but Not Serum Progranulin, Is Reduced in GRN-Negative Frontotemporal Dementia.

Wilke, C. ; Gillardon, F. ; Deuschle, C. ; Hobert, M. A. ; Jansen, I. E.DZNE* ; Metzger, F. G. ; Heutink, P.DZNE* ; Gasser, T. ; Maetzler, W. ; Blauwendraat, C.DZNE* ; Synofzik, M.

2017
Karger Basel

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Please use a persistent id in citations: doi:10.1159/000448896

Abstract: 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.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).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.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.

Keyword(s): Aged (MeSH) ; Female (MeSH) ; Frontotemporal Dementia: blood (MeSH) ; Frontotemporal Dementia: cerebrospinal fluid (MeSH) ; Frontotemporal Dementia: genetics (MeSH) ; Humans (MeSH) ; Intercellular Signaling Peptides and Proteins: blood (MeSH) ; Intercellular Signaling Peptides and Proteins: cerebrospinal fluid (MeSH) ; Intercellular Signaling Peptides and Proteins: genetics (MeSH) ; Male (MeSH) ; Middle Aged (MeSH) ; Mutation (MeSH) ; Mutation, Missense (MeSH) ; Phosphorylation (MeSH) ; Polymorphism, Single Nucleotide (MeSH) ; Progranulins (MeSH) ; tau Proteins: cerebrospinal fluid (MeSH) ; tau Proteins: metabolism (MeSH) ; GRN protein, human ; Intercellular Signaling Peptides and Proteins ; MAPT protein, human ; Progranulins ; tau Proteins

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Contributing Institute(s):

1. Genome Biology of Neurodegenerative Diseases (AG Heutink 1)

Research Program(s):

1. 345 - Population Studies and Genetics (POF3-345) (POF3-345)

Appears in the scientific report 2017

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Ebsco Academic Search ; IF < 5 ; JCR ; National-Konsortium ; SCOPUS ; Web of Science Core Collection

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