Different chronic stress paradigms converge on endogenous TDP43 cleavage and aggregation
Authors:
Niccolò Candelise (1,2,3), Daniela Caissutti (2), Henri Zenuni (4), Valentina Nesci (3,4), Silvia Scaricamazza (3), Illari Salvatori (3), Zaira Spinello (2), Vincenzo Mattei (5), Tina Garofalo (2), Alberto Ferri (3,6), Cristiana Valle (3,6), Roberta Misasi (2)
Organisations:
1: Istituto Superiore di Sanità, Italy, National Center for Drug Research and Evaluation
2: Department of Experimental Medicine, "Sapienza" University of Rome
3: IRCCS Fondazione Santa Lucia
4: Department of Systems Medicine, “Tor Vergata” University of Rome
5: Biomedicine and Advanced Technologies Rieti Center, Sabina Universitas
6: Institute of Translational Pharmacology (IFT), Consiglio Nazionale delle Ricerche (CNR)
Presenting author:
Niccolò Candelise
Exposition date:
Saturday, September 16, 2023
Exposition position:
128/2
The TAR-DNA binding protein (TDP43) is a nuclear protein whose cytoplasmic inclusions are hallmarks of Amyotrophic Lateral Sclerosis (ALS). Acute stress in cells causes TDP43 mobilization to the cytoplasm and its aggregation through different routes. Although acute stress elicits a strong phenotype, is far from recapitulating the years-long aggregation process. We applied different chronic stress protocols and described TDP43 aggregation in a human neuroblastoma cell line by combining solubility assays, thioflavin-based microscopy and flow cytometry. This approach allowed us to detect, for the first time to our knowledge in vitro, the formation of 25 kDa C-terminal fragment of TDP43, a pathogenic hallmark of ALS. Our results indicate that chronic stress, compared to the more common acute stress paradigm, better recapitulates the cell biology of TDP43 proteinopathies. Moreover, we optimized a protocol for the detection of bona fide prions in living cells, suggesting that TDP43 may form amyloids as a stress response.
