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

By M.E. Cicardi, R. Cristofani, P. Rusmini, M. Meroni, V. Ferrari, G. Vezzoli, B. Tedesco, M. Piccolella, E. Messi, M. Galbiati, A. Boncoraglio, S. Carra, V. Crippa and A. Poletti

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 \u201cprion-like\u201d 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

Topics: HSPB8, autophagy, protein misfolding, aggregation, neurodegeneration, proteasome, ALS, TDP43, trehalose, Settore BIO/13 - Biologia Applicata, Settore BIO/09 - Fisiologia
Publisher: 'Springer Science and Business Media LLC'
Year: 2018
DOI identifier: 10.1038/s41598-018-29658-2
OAI identifier: oai:air.unimi.it:2434/585247

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