Motor neuron degeneration, severe myopathy and TDP-43 increase in a transgenic pig model of SOD1-linked familiar ALS

NEUROBIOLOGY OF DISEASE

卷:124

Article

Crociaraa, Paola¹  Chieppa, Maria Novella¹  Vallino Costassa, Elena¹  Berrone, Elena¹  Gallo, Marina¹  Lo Faro, Monica¹  Pintore, Maria Domenica¹  Iulini, Barbara¹  D'Angelo, Antonio²  Perona, Giovanni²  Botter, Alberto³  Formicola, Donato⁴  Rainoldi, Alberto⁴  Paulis, Marianna^5,6  Vezzoni, Paolo^5,6  Meli, Federica⁷  Peverali, Fiorenzo Antonio⁷  Bendotti, Caterina⁸  Trolese, Maria Chiara⁸  Pasetto, Laura⁸  Bonetto, Valentina⁸  Lazzari, Giovanna^9,10  Duchi, Roberto⁹  Perota, Andrea⁹  Lagutina, Irma⁹  Quadalti, Corinne⁹  Gennero, Maria Silvia¹  Dezzutto, Daniela¹  Desiato, Rosanna¹  Boido, Marina¹¹  Ghibaudi, Matilde¹¹  Valentini, Maria Consuelo¹²  Caramelli, Maria¹  Galli, Cesare^9,10  Casalone, Cristina¹  Corona, Cristiano¹ 

[1] Ist Zooprofilatt Sperimentale Piemonte Liguria &, Via Bologna 148, I-10154 Turin, TO, Italy

[2] Univ Turin, Dept Vet Sci, Largo Paolo Braccini 2, I-10095 Grugliasco, TO, Italy

[3] Politecn Torino, Lab Ingn Sistema Neuromuscolare LISIN, Corso Castelfidardo 42-A, I-10138 Turin, TO, Italy

[4] Univ Turin, Sch Exercise & Sport Sci, Dept Med Sci, NeuroMuscularFunct Res Grp, Piazza Gian Lorenzo Bernini 12, I-10143 Turin, TO, Italy

[5] CNR, Milan Unit, Ist Ric Genet & Biomed, Via Fantoli 16-15, I-20138 Milan, MI, Italy

[6] Humanitas Clin & Res Ctr, Via Manzoni 56, I-20089 Rozzano, MI, Italy

[7] CNR, Ist Genet Mol, Via Abbiategrasso 207, I-27100 Pavia, PV, Italy

[8] IRCCS Ist Ric Farmacol Mario Negri, Via La Masa 19, I-20156 Milan, MI, Italy

[9] Avantea, Via Porcellasco 7F, I-26100 Cremona, CR, Italy

[10] Fdn Avantea, Via Porcellasco 7F, I-26100 Cremona, CR, Italy

[11] Univ Turin, NICO, Dept Neurosci, Reg Gonzole 10, I-10043 Orbassano, TO, Italy

[12] AOU Citta Salute & Sci, Dept Neuroradiol, Corso Bramante 88, I-10126 Turin, TO, Italy

关键词: SOD1;    Transgenic pig;    Amyotrophic lateral sclerosis;    ALS;    TDP-43;   

DOI  :  10.1016/j.nbd.2018.11.021

来源: Elsevier

【 摘 要 】

Amyotrophic Lateral Sclerosis (ALS) is a neural disorder gradually leading to paralysis of the whole body. Alterations in superoxide dismutase SOD1 gene have been linked with several variants of familial ALS. Here, we investigated a transgenic (Tg) cloned swine model expressing the human pathological hSOD1(G93A) allele. As in patients, these Tg pigs transmitted the disease to the progeny with an autosomal dominant trait and showed ALS onset from about 27 months of age. Post mortem analysis revealed motor neuron (MN) degeneration, gliosis and hSOD1 protein aggregates in brainstem and spinal cord. Severe skeletal muscle pathology including necrosis and inflammation was observed at the end stage, as well. Remarkably, as in human patients, these Tg pigs showed a quite long presymptomatic phase in which gradually increasing amounts of TDP-43 were detected in peripheral blood mononuclear cells. Thus, this transgenic swine model opens the unique opportunity to investigate ALS biomarkers even before disease onset other than testing novel drugs and possible medical devices.

【 授权许可】

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