Journal
SCIENTIFIC REPORTS
Volume 8, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-018-29658-2
Keywords
-
Categories
Funding
- Fondazione Telethon, Italy [GGP14039]
- Fondazione Cariplo, Italy [2014-0686, 2017_0747]
- Fondazione AriSLA, Italy [ALS_HSPB8]
- Association Francaise contre les Myopathies, France (AFM Telethon) [16406]
- Universita degli Studi di Milano e piano di sviluppo UNIMI - linea B
- Italian Ministry of University and Research (MIUR), PRIN - Progetti di ricerca di interesse nazionale [2015LFPNMN]
- Fondo per il Finanziamento delle Attivita Base di Ricerca (FFABR) (MIUR)
- Agenzia Italiana del Farmaco (AIFA) (Co_ALS)
- Italian Ministry of Health [GR-2011-02347198]
- Fondazione Regionale per la Ricerca Biomedica (FRRB) (Regione Lombardia, TRANS_ALS) [2015-0023]
- European Molecular Biology Organization (EMBO) [537-2015]
- JPND
- European Union's Horizon 2020 research and innovation programme [643417, 01ED1601A]
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available