Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that primarily affects motoneurons, while non-neuronal cells may contribute to disease onset and progression. Most ALS cases are characterized by the mislocalization and aggregation of the TAR DNA binding protein 43 (TDP-43) in affected cells. TDP-43 aggregates contain C-terminal TDP-43 fragments of 35 kDa (TDP-35) and 25 kDa (TDP-25) and have been mainly studied in motoneurons, while little is currently known about their rate of accumulation and clearance in myoblasts. Here, we performed a comparative study in immortalized motoneuronal like (NSC34; i-motoneurons) cells and stabilized myoblasts (C2C12; s-myoblasts) to evaluate if these two cell types differentially accumulate and clear TDP forms. The most aggregating specie in i-motoneurons is the TDP-25 fragment, mainly constituted by the “prion-like” domain of TDP-43. To a lower extent, TDP-25 also aggregates in s-myoblasts. In both cell types, all TDP species are cleared by proteasome, but TDP-25 impairs autophagy. Interestingly, the routing of TDP-25 fragment to proteasome, by overexpressing BAG1, or to autophagy, by overexpressing HSPB8 or BAG3 decreased its accumulation in both cell types. These results demonstrate that promoting the chaperone-assisted clearance of ALS-linked proteins is beneficial not only in motoneurons but also in myoblasts.

Tdp-25 Routing to Autophagy and Proteasome Ameliorates its Aggregation in Amyotrophic Lateral Sclerosis Target Cells / Cicardi, Maria Elena; Cristofani, Riccardo; Rusmini, Paola; Meroni, Marco; Ferrari, Veronica; Vezzoli, Giulia; Tedesco, Barbara; Piccolella, Margherita; Messi, Elio; Galbiati, Mariarita; Boncoraglio, Alessandra; Carra, Serena; Crippa, Valeria; Poletti, Angelo. - In: SCIENTIFIC REPORTS. - ISSN 2045-2322. - 8:1(2018), pp. 1-16. [10.1038/s41598-018-29658-2]

Tdp-25 Routing to Autophagy and Proteasome Ameliorates its Aggregation in Amyotrophic Lateral Sclerosis Target Cells

Carra, Serena;
2018

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that primarily affects motoneurons, while non-neuronal cells may contribute to disease onset and progression. Most ALS cases are characterized by the mislocalization and aggregation of the TAR DNA binding protein 43 (TDP-43) in affected cells. TDP-43 aggregates contain C-terminal TDP-43 fragments of 35 kDa (TDP-35) and 25 kDa (TDP-25) and have been mainly studied in motoneurons, while little is currently known about their rate of accumulation and clearance in myoblasts. Here, we performed a comparative study in immortalized motoneuronal like (NSC34; i-motoneurons) cells and stabilized myoblasts (C2C12; s-myoblasts) to evaluate if these two cell types differentially accumulate and clear TDP forms. The most aggregating specie in i-motoneurons is the TDP-25 fragment, mainly constituted by the “prion-like” domain of TDP-43. To a lower extent, TDP-25 also aggregates in s-myoblasts. In both cell types, all TDP species are cleared by proteasome, but TDP-25 impairs autophagy. Interestingly, the routing of TDP-25 fragment to proteasome, by overexpressing BAG1, or to autophagy, by overexpressing HSPB8 or BAG3 decreased its accumulation in both cell types. These results demonstrate that promoting the chaperone-assisted clearance of ALS-linked proteins is beneficial not only in motoneurons but also in myoblasts.
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Tdp-25 Routing to Autophagy and Proteasome Ameliorates its Aggregation in Amyotrophic Lateral Sclerosis Target Cells / Cicardi, Maria Elena; Cristofani, Riccardo; Rusmini, Paola; Meroni, Marco; Ferrari, Veronica; Vezzoli, Giulia; Tedesco, Barbara; Piccolella, Margherita; Messi, Elio; Galbiati, Mariarita; Boncoraglio, Alessandra; Carra, Serena; Crippa, Valeria; Poletti, Angelo. - In: SCIENTIFIC REPORTS. - ISSN 2045-2322. - 8:1(2018), pp. 1-16. [10.1038/s41598-018-29658-2]
Cicardi, Maria Elena; Cristofani, Riccardo; Rusmini, Paola; Meroni, Marco; Ferrari, Veronica; Vezzoli, Giulia; Tedesco, Barbara; Piccolella, Margherita; Messi, Elio; Galbiati, Mariarita; Boncoraglio, Alessandra; Carra, Serena; Crippa, Valeria; Poletti, Angelo
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11380/1167651
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