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.

Sabatelli, M., Zollino, M., Conte, A., Del Grande, A., Marangi, G., Lucchini, M., Mirabella, M., Romano, A., Piacentini, R., Bisogni, G., Lattante, S., Luigetti, M., Rossini, P. M., Moncada, A., Primary fibroblasts cultures reveal TDP-43 abnormalities in amyotrophic lateral sclerosis patients with and without SOD1 mutations, <<NEUROBIOLOGY OF AGING>>, 2015; 36 (5): e5-e13. [doi:10.1016/j.neurobiolaging.2015.02.009] [http://hdl.handle.net/10807/71638]

Primary fibroblasts cultures reveal TDP-43 abnormalities in amyotrophic lateral sclerosis patients with and without SOD1 mutations

Sabatelli, Mario;Zollino, Marcella;Conte, Amelia;Del Grande, Alessandra;Marangi, Giuseppe;Lucchini, Matteo;Mirabella, Massimiliano;Romano, Angela;Piacentini, Roberto;Bisogni, Giulia;Lattante, Serena;Luigetti, Marco;Rossini, Paolo Maria;Moncada, Alice
2015

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.
Inglese
Sabatelli, M., Zollino, M., Conte, A., Del Grande, A., Marangi, G., Lucchini, M., Mirabella, M., Romano, A., Piacentini, R., Bisogni, G., Lattante, S., Luigetti, M., Rossini, P. M., Moncada, A., Primary fibroblasts cultures reveal TDP-43 abnormalities in amyotrophic lateral sclerosis patients with and without SOD1 mutations, <<NEUROBIOLOGY OF AGING>>, 2015; 36 (5): e5-e13. [doi:10.1016/j.neurobiolaging.2015.02.009] [http://hdl.handle.net/10807/71638]
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10807/71638
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