title: Primary fibroblasts cultures reveal TDP-43 abnormalities in amyotrophic lateral sclerosis patients with and without SOD1 mutations.
abstract: TAR DNA-binding protein 43 (TDP-43) is a major component of the pathologic inclusions observed in the motor neurons of amyotrophic lateral sclerosis (ALS) patients. We examined TDP-43 expression in primary fibroblasts cultures from 22 ALS patients, including cases with SOD1 (n = 4), TARDBP (n = 4), FUS (n = 2), and C9ORF72 (n = 3) mutations and 9 patients without genetic defect. By using a phosphorylation-independent antibody, 15 patients showed notable alterations of TDP-43 level in the nuclear or cytoplasmic compartments. In particular, a marked accumulation of TDP-43 was observed in the cytoplasm of all cases with C9ORF72 and TARDBP mutations, 1 patient with FUS mutation and 3 patients without genetic defect. Patients with SOD1 mutations revealed a significant reduction of TDP-43 in the nuclei without cytoplasmic mislocalization. These changes were associated with the presence of truncated and phosphorylated TDP-43 species. Our results show that fibroblasts recapitulate some of hallmark TDP-43 abnormalities observed in neuronal cells. The reduction of full-length TDP-43 level in mutant SOD1 cells indicates that at least some SOD1 mutations alter TDP-43 metabolism.
authors: Istituto di Neurologia, Università Cattolica del Sacro Cuore, Rome, Italy. Electronic address: msabatelli@rm.unicatt.it.
authors: Mario
authors: M
authors: Sabatelli
authors: Istituto di Genetica Medica, Università Cattolica del Sacro Cuore, Rome, Italy.
authors: Marcella
authors: M
authors: Zollino
authors: Istituto di Neurologia, Università Cattolica del Sacro Cuore, Rome, Italy.
authors: Amelia
authors: A
authors: Conte
authors: Istituto di Neurologia, Università Cattolica del Sacro Cuore, Rome, Italy.
authors: Alessandra
authors: A
authors: Del Grande
authors: Istituto di Genetica Medica, Università Cattolica del Sacro Cuore, Rome, Italy.
authors: Giuseppe
authors: G
authors: Marangi
authors: Istituto di Neurologia, Università Cattolica del Sacro Cuore, Rome, Italy.
authors: Matteo
authors: M
authors: Lucchini
authors: Istituto di Neurologia, Università Cattolica del Sacro Cuore, Rome, Italy.
authors: Massimiliano
authors: M
authors: Mirabella
authors: Istituto di Neurologia, Università Cattolica del Sacro Cuore, Rome, Italy.
authors: Angela
authors: A
authors: Romano
authors: Istituto di Fisiologia Umana, Università Cattolica del Sacro Cuore, Rome, Italy.
authors: Roberto
authors: R
authors: Piacentini
authors: Istituto di Neurologia, Università Cattolica del Sacro Cuore, Rome, Italy.
authors: Giulia
authors: G
authors: Bisogni
authors: Istituto di Genetica Medica, Università Cattolica del Sacro Cuore, Rome, Italy.
authors: Serena
authors: S
authors: Lattante
authors: Istituto di Neurologia, Università Cattolica del Sacro Cuore, Rome, Italy.
authors: Marco
authors: M
authors: Luigetti
authors: Istituto di Neurologia, Università Cattolica del Sacro Cuore, Rome, Italy; IRCCS S. Raffaele-Pisana and Casa di Cura S Raffaele, Cassino, Italy.
authors: Paolo Maria
authors: PM
authors: Rossini
authors: Istituto di Genetica Medica, Università Cattolica del Sacro Cuore, Rome, Italy.
authors: Alice
authors: A
authors: Moncada
mesh_terms: D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D002478:Cells, Cultured; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D002479:Inclusion Bodies; D008297:Male; D008875:Middle Aged; D009046:Motor Neurons / Q000166:cytology; D009154:Mutation; D013482:Superoxide Dismutase / Q000235:genetics* / Q000502:physiology; D000072105:Superoxide Dismutase-1
chemical_list: D004268:DNA-Binding Proteins; C000606290:SOD1 protein, human; C000598624:TARDBP protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
keywords: 3′ UTR; Amyotrophic lateral sclerosis; Fibroblast culture; TARDBP; TDP-43