title: Reduced Tau protein expression is associated with frontotemporal degeneration with progranulin mutation.
abstract: Reduction of Tau protein expression was described in 2003 by Zhukareva et al. in a variant of frontotemporal lobar degeneration (FTLD) referred to as diagnosis of dementia lacking distinctive histopathology, then re-classified as FTLD with ubiquitin inclusions. However, the analysis of Tau expression in FTLD has not been reconsidered since then. Knowledge of the molecular basis of protein aggregates and genes that are mutated in the FTLD spectrum would enable to determine whether the "Tau-less" is a separate pathological entity or if it belongs to an existing subclass of FTLD. To address this question, we have analyzed Tau expression in the frontal brain areas from control, Alzheimer's disease and FTLD cases, including FTLD- Tau (MAPT), FTLD-TDP (sporadic, FTLD-TDP-GRN, FTLD-TDP-C9ORF72) and sporadic FTLD-FUS, using western blot and 2D-DIGE (Two-Dimensional fluorescence Difference Gel Electrophoresis) approaches. Surprisingly, we found that most of the FTLD-TDP-GRN brains are characterized by a huge reduction of Tau protein expression without any decrease in Tau mRNA levels. Interestingly, only cases affected by point mutations, rather than cases with total deletion of one GRN allele, seem to be affected by this reduction of Tau protein expression. Moreover, proteomic analysis highlighted correlations between reduced Tau protein level, synaptic impairment and massive reactive astrogliosis in these FTLD-GRN cases. Consistent with a recent study, our data also bring new insights regarding the role of progranulin in neurodegeneration by suggesting its involvement in lysosome and synaptic regulation. Together, our results demonstrate a strong association between progranulin deficiency and reduction of Tau protein expression that could lead to severe neuronal and glial dysfunctions. Our study also indicates that this FTLD-TDP-GRN subgroup could be part as a distinct entity of FTLD classification.
authors.affiliation: University of Lille, Inserm, CHU-Lille, F-59000, Lille, France.
authors.forename: Anthony
authors.initials: A
authors.lastname: Papegaey
authors.affiliation: University of Lille, Inserm, CHU-Lille, F-59000, Lille, France.
authors.forename: Sabiha
authors.initials: S
authors.lastname: Eddarkaoui
authors.affiliation: University of Lille, Inserm, CHU-Lille, F-59000, Lille, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Deramecourt
authors.affiliation: University of Lille, Inserm, CHU-Lille, F-59000, Lille, France.
authors.forename: Francisco-Jose
authors.initials: FJ
authors.lastname: Fernandez-Gomez
authors.affiliation: University of Lille, Inserm, CHU-Lille, F-59000, Lille, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Pantano
authors.affiliation: University of Lille, Inserm, CHU-Lille, F-59000, Lille, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Obriot
authors.affiliation: University of Lille, Inserm, CHU-Lille, F-59000, Lille, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Machala
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Hôpital Pitié-Salpêtrière, Paris, France.|INSERM UMRS_1127, Hôpital Pitié-Salpêtrière, Paris, France.|CNRS UMR_7225, Hôpital Pitié-Salpêtrière, Paris, France.|AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.|ICM, Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Anquetil
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Hôpital Pitié-Salpêtrière, Paris, France.|INSERM UMRS_1127, Hôpital Pitié-Salpêtrière, Paris, France.|CNRS UMR_7225, Hôpital Pitié-Salpêtrière, Paris, France.|AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.|ICM, Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Camuzat
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Hôpital Pitié-Salpêtrière, Paris, France.|INSERM UMRS_1127, Hôpital Pitié-Salpêtrière, Paris, France.|CNRS UMR_7225, Hôpital Pitié-Salpêtrière, Paris, France.|AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.|ICM, Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.affiliation: University of Lille, Inserm, CHU-Lille, F-59000, Lille, France.
authors.forename: Claude-Alain
authors.initials: CA
authors.lastname: Maurage
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Hôpital Pitié-Salpêtrière, Paris, France.|INSERM UMRS_1127, Hôpital Pitié-Salpêtrière, Paris, France.|CNRS UMR_7225, Hôpital Pitié-Salpêtrière, Paris, France.|AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.|ICM, Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Le Ber
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Hôpital Pitié-Salpêtrière, Paris, France.|INSERM UMRS_1127, Hôpital Pitié-Salpêtrière, Paris, France.|CNRS UMR_7225, Hôpital Pitié-Salpêtrière, Paris, France.|AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.|ICM, Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Duyckaerts
authors.affiliation: University of Lille, Inserm, CHU-Lille, F-59000, Lille, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Buée
authors.affiliation: University of Lille, Inserm, CHU-Lille, F-59000, Lille, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Sergeant
authors.affiliation: University of Lille, Inserm, CHU-Lille, F-59000, Lille, France. valerie.buee-scherrer@inserm.fr.|Université Artois, Faculté Jean Perrin, F-62307, Lens, France. valerie.buee-scherrer@inserm.fr.|Inserm UMRS1172 - Alzheimer & Tauopathies, Faculty of Medecine-Research Pole, University of Lille, Place de Verdun, F-59045, Lille cedex, France. valerie.buee-scherrer@inserm.fr.
authors.forename: Valérie
authors.initials: V
authors.lastname: Buée-Scherrer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism* / Q000473:pathology; D057174:Frontotemporal Lobar Degeneration / Q000145:classification / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D015870:Gene Expression; D005911:Gliosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D017354:Point Mutation; D000077153:Progranulins; D020543:Proteome; D012333:RNA, Messenger / Q000378:metabolism; D017384:Sequence Deletion; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; C054369:MAPT protein, human; D000077153:Progranulins; D020543:Proteome; D012333:RNA, Messenger; D016875:tau Proteins
keywords: Astrogliosis; Frontotemporal lobar degeneration; Progranulin; Synaptic impairment; Tau protein