Extracellular vesicles (EVs) play a central role in neurodegenerative diseases (NDs) since they may either spread the pathology or contribute to the intracellular protein quality control (PQC) system for the cellular clearance of NDs-associated proteins. Here, we investigated the crosstalk between large (LVs) and small (SVs) EVs and PQC in the disposal of TDP-43 and its FTLD and ALS-associated C-terminal fragments (TDP-35 and TDP-25). By taking advantage of neuronal cells (NSC-34 cells), we demonstrated that both EVs types, but particularly LVs, contained TDP-43, TDP-35 and TDP-25. When the PQC system was inhibited, as it occurs in NDs, we found that TDP-35 and TDP-25 secretion via EVs increased. In line with this observation, we specifically detected TDP-35 in EVs derived from plasma of FTLD patients. Moreover, we demonstrated that both neuronal and plasma-derived EVs transported components of the chaperone-assisted selective autophagy (CASA) complex (HSP70, BAG3 and HSPB8). Neuronal EVs also contained the autophagy-related MAP1LC3B-II protein. Notably, we found that, under PQC inhibition, HSPB8, BAG3 and MAP1LC3B-II secretion paralleled that of TDP-43 species. Taken together, our data highlight the role of EVs, particularly of LVs, in the disposal of disease-associated TDP-43 species, and suggest a possible new role for the CASA complex in NDs.

Neurodegenerative Disease-Associated TDP-43 Fragments Are Extracellularly Secreted with CASA Complex Proteins / E. Casarotto, D. Sproviero, E. Corridori, M.C. Gagliani, M. Cozzi, M. Chierichetti, R. Cristofani, V. Ferrari, M. Galbiati, F. Mina, M. Piccolella, P. Rusmini, B. Tedesco, S. Gagliardi, K. Cortese, C. Cereda, A. Poletti, V. Crippa. - In: CELLS. - ISSN 2073-4409. - 11:3(2022 Feb 02), pp. 516.1-516.19. [10.3390/cells11030516]

Neurodegenerative Disease-Associated TDP-43 Fragments Are Extracellularly Secreted with CASA Complex Proteins

Casarotto E.;Corridori E.;Cozzi M.;Chierichetti M.;Cristofani R.;Ferrari V.;Galbiati M.;Mina F.;Piccolella M.;Rusmini P.;Tedesco B.;Gagliardi S.;Cortese K.;Poletti A.;Crippa V.
2022-02-02

Abstract

Extracellular vesicles (EVs) play a central role in neurodegenerative diseases (NDs) since they may either spread the pathology or contribute to the intracellular protein quality control (PQC) system for the cellular clearance of NDs-associated proteins. Here, we investigated the crosstalk between large (LVs) and small (SVs) EVs and PQC in the disposal of TDP-43 and its FTLD and ALS-associated C-terminal fragments (TDP-35 and TDP-25). By taking advantage of neuronal cells (NSC-34 cells), we demonstrated that both EVs types, but particularly LVs, contained TDP-43, TDP-35 and TDP-25. When the PQC system was inhibited, as it occurs in NDs, we found that TDP-35 and TDP-25 secretion via EVs increased. In line with this observation, we specifically detected TDP-35 in EVs derived from plasma of FTLD patients. Moreover, we demonstrated that both neuronal and plasma-derived EVs transported components of the chaperone-assisted selective autophagy (CASA) complex (HSP70, BAG3 and HSPB8). Neuronal EVs also contained the autophagy-related MAP1LC3B-II protein. Notably, we found that, under PQC inhibition, HSPB8, BAG3 and MAP1LC3B-II secretion paralleled that of TDP-43 species. Taken together, our data highlight the role of EVs, particularly of LVs, in the disposal of disease-associated TDP-43 species, and suggest a possible new role for the CASA complex in NDs.
Amyotrophic lateral sclerosis (ALS); Bcl-2 associated athanogene 3 (BAG3); Chaperone-assisted selective autophagy (CASA); Extracellular vesicles (EVs); Frontotemporal lobar degeneration (FTLD); Heat shock protein 70 (HSP70); Small heat shock protein B8 (HSPB8); Transactive response DNA-binding protein 43 (TDP-43)
Settore BIO/13 - Biologia Applicata
Settore BIO/09 - Fisiologia
INTLI21APOLE_01 - The involvement of the small heat shock protein HSPB8 in amyotrophic lateral sclerosis - POLETTI, ANGELO - INTLI - Finanziamenti internazionali - 2021
CAR_RIC18VCRIP_01 - Extracellular vescicles in the pathogenesis of frontotemporal dementia - CRIPPA, VALERIA - CAR_RIC - Bandi Fondazione Cariplo - 2018
PRIN201719APOLE_01 - The interplay between the “rna/protein quality control system” and “exosomes” as a spreading mechanism in amyotrophic lateral sclerosis (EX_ALS) - POLETTI, ANGELO - PRIN2017 - PRIN bando 2017 - 2019
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/905158
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