title: Profiling of ubiquitination pathway genes in peripheral cells from patients with frontotemporal dementia due to C9ORF72 and GRN mutations.
abstract: We analysed the expression levels of 84 key genes involved in the regulated degradation of cellular protein by the ubiquitin-proteasome system in peripheral cells from patients with frontotemporal dementia (FTD) due to C9ORF72 and GRN mutations, as compared with sporadic FTD and age-matched controls. A SABiosciences PCR array was used to investigate the transcription profile in a discovery population consisting of six patients each in C9ORF72, GRN, sporadic FTD and age-matched control groups. A generalized down-regulation of gene expression compared with controls was observed in C9ORF72 expansion carriers and sporadic FTD patients. In particular, in both groups, four genes, UBE2I, UBE2Q1, UBE2E1 and UBE2N, were down-regulated at a statistically significant (p < 0.05) level. All of them encode for members of the E2 ubiquitin-conjugating enzyme family. In GRN mutation carriers, no statistically significant deregulation of ubiquitination pathway genes was observed, except for the UBE2Z gene, which displays E2 ubiquitin conjugating enzyme activity, and was found to be statistically significant up-regulated (p = 0.006). These preliminary results suggest that the proteasomal degradation pathway plays a role in the pathogenesis of FTD associated with TDP-43 pathology, although different proteins are altered in carriers of GRN mutations as compared with carriers of the C9ORF72 expansion.
authors.affiliation: Neurology Unit, Department of Pathophysiology and Transplantation, "Dino Ferrari" Center, University of Milan, Fondazione Ca' Granda, IRCCS Ospedale Maggiore Policlinico, Milan 20122, Italy. maria.serpente@policlinico.mi.it.
authors.forename: Maria
authors.initials: M
authors.lastname: Serpente
authors.affiliation: Neurology Unit, Department of Pathophysiology and Transplantation, "Dino Ferrari" Center, University of Milan, Fondazione Ca' Granda, IRCCS Ospedale Maggiore Policlinico, Milan 20122, Italy. chiara.fenoglio@unimi.it.
authors.forename: Chiara
authors.initials: C
authors.lastname: Fenoglio
authors.affiliation: Neurology Unit, Department of Pathophysiology and Transplantation, "Dino Ferrari" Center, University of Milan, Fondazione Ca' Granda, IRCCS Ospedale Maggiore Policlinico, Milan 20122, Italy. sara.cioffi@unimi.it.
authors.forename: Sara M G
authors.initials: SM
authors.lastname: Cioffi
authors.affiliation: Neurology Unit, Department of Pathophysiology and Transplantation, "Dino Ferrari" Center, University of Milan, Fondazione Ca' Granda, IRCCS Ospedale Maggiore Policlinico, Milan 20122, Italy. rossana.bonsi@unimi.it.
authors.forename: Rossana
authors.initials: R
authors.lastname: Bonsi
authors.affiliation: Neurology Unit, Department of Pathophysiology and Transplantation, "Dino Ferrari" Center, University of Milan, Fondazione Ca' Granda, IRCCS Ospedale Maggiore Policlinico, Milan 20122, Italy. andrea.arighi@yahoo.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Arighi
authors.affiliation: Neurology Unit, Department of Pathophysiology and Transplantation, "Dino Ferrari" Center, University of Milan, Fondazione Ca' Granda, IRCCS Ospedale Maggiore Policlinico, Milan 20122, Italy. giorgiofumagalli@hotmail.com.
authors.forename: Giorgio G
authors.initials: GG
authors.lastname: Fumagalli
authors.affiliation: Neurology Unit, Department of Pathophysiology and Transplantation, "Dino Ferrari" Center, University of Milan, Fondazione Ca' Granda, IRCCS Ospedale Maggiore Policlinico, Milan 20122, Italy. lauraghezzi@me.com.
authors.forename: Laura
authors.initials: L
authors.lastname: Ghezzi
authors.affiliation: Neurology Unit, Department of Pathophysiology and Transplantation, "Dino Ferrari" Center, University of Milan, Fondazione Ca' Granda, IRCCS Ospedale Maggiore Policlinico, Milan 20122, Italy. elio.scarpini@unimi.it.
authors.forename: Elio
authors.initials: E
authors.lastname: Scarpini
authors.affiliation: Neurology Unit, Department of Pathophysiology and Transplantation, "Dino Ferrari" Center, University of Milan, Fondazione Ca' Granda, IRCCS Ospedale Maggiore Policlinico, Milan 20122, Italy. daniela.galimberti@unimi.it.
authors.forename: Daniela
authors.initials: D
authors.lastname: Galimberti
mesh_terms: D000368:Aged; D000073885:C9orf72 Protein; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000473:pathology; D005838:Genotype; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D000077153:Progranulins; D011506:Proteins / Q000235:genetics*; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination; D000098843:Ubiquitin-Conjugating Enzyme UBC9
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004268:DNA-Binding Proteins; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D011506:Proteins; C489963:UBE2E1 protein, human; C471607:UBE2N protein, human; C581814:UBE2Q1 protein, human; D044763:Ubiquitin-Conjugating Enzymes; D000098843:Ubiquitin-Conjugating Enzyme UBC9