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 / 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, A. Poletti. - In: SCIENTIFIC REPORTS. - ISSN 2045-2322. - 8:1(2018).
|Titolo:||Tdp-25 Routing to Autophagy and Proteasome Ameliorates its Aggregation in Amyotrophic Lateral Sclerosis Target Cells|
CICARDI, MARIA ELENA (Primo)
CRISTOFANI, RICCARDO MARIA (Secondo)
CRIPPA, VALERIA (Penultimo)
POLETTI, ANGELO (Ultimo) [Funding Acquisition] (Corresponding)
|Parole Chiave:||HSPB8; autophagy; protein misfolding; aggregation; neurodegeneration; proteasome; ALS; TDP43; trehalose|
|Settore Scientifico Disciplinare:||Settore BIO/13 - Biologia Applicata|
Settore BIO/09 - Fisiologia
|Progetto:||RAN translation of normal and expanded nucleotide repeat containing transcripts to neurotoxic polypetides in neurodegenerative diseases|
|Data di pubblicazione:||2018|
|Centro di ricerca:||Centro Interdipartimentale di Eccellenza per le Malattie Neurodegenerative CEND|
Centro Interuniversitario di Ricerca sulle Basi Molecolari delle Malattie Neurodegenerative
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1038/s41598-018-29658-2|
|Appare nelle tipologie:||01 - Articolo su periodico|