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

• Published in: Scientific reports 2018-08, Vol.8 (1), p.12390-16, Article 12390
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/109; 13/89; 14/19; 14/34; 14/35; 14/5; 38/77; 42; 42/109; 42/34; 45; 631/378/2632/1664; 692/617/375/1917/1285; 82/80; Aggregates; Amyotrophic lateral sclerosis; Autophagy; Comparative studies; Humanities and Social Sciences; Motor neurons; multidisciplinary; Myoblasts; Phagocytosis; Proteasomes; Science; Science (multidisciplinary)
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-29658-2

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.