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Pathological 25 kDa C-Terminal Fragments of TDP-43 Are Present in Lymphoblastoid Cell Lines and Extracellular Vesicles from Patients Affected by Frontotemporal Lobar Degeneration and Neuronal Ceroidolipofuscinosis Carrying a GRN Mutation

Authors :
Sara Cimini
Sonia Bellini
Claudia Saraceno
Luisa Benussi
Roberta Ghidoni
Silvia Clara Giliani
Gianfranco Puoti
Laura Canafoglia
Giorgio Giaccone
Giacomina Rossi
Cimini, Sara
Bellini, Sonia
Saraceno, Claudia
Benussi, Luisa
Ghidoni, Roberta
Giliani, Silvia Clara
Puoti, Gianfranco
Canafoglia, Laura
Giaccone, Giorgio
Rossi, Giacomina
Source :
International Journal of Molecular Sciences; Volume 23; Issue 22; Pages: 13753
Publication Year :
2022
Publisher :
Multidisciplinary Digital Publishing Institute, 2022.

Abstract

Frontotemporal lobar degeneration (FTLD) is a complex disease, characterized by progressive degeneration of frontal and temporal lobes. Mutations in progranulin (GRN) gene have been found in up to 50% of patients with familial FTLD. Abnormal deposits of post-translationally-modified TAR DNA-binding protein of 43 kDa (TDP-43) represent one of the main hallmarks of the brain pathology. To investigate in peripheral cells the presence of the different TDP-43 forms, especially the toxic 25 kDa fragments, we analyzed lymphoblastoid cell lines (LCLs) and the derived extracellular vesicles (EVs) from patients carrying a GRN mutation, together with wild-type (WT) healthy controls. After characterizing EV sizes and concentrations by nanoparticle tracking analysis, we investigated the levels of different forms of the TDP-43 protein in LCLs and respective EVs by Western blot. Our results showed a trend of concentration decreasing in EVs derived from GRN-mutated LCLs, although not reaching statistical significance. A general increase in p-TDP-43 levels in GRN-mutated LCLs and EVs was observed. In particular, the toxic 25 kDa fragments of p-TDP-43 were only present in GRN-mutated LCLs and were absent in the WT controls. Furthermore, these fragments appeared to be more concentrated in EVs than in LCLs, suggesting a relevant role of EVs in spreading pathological molecules between cells.

Details

Language :
English
ISSN :
14220067
Database :
OpenAIRE
Journal :
International Journal of Molecular Sciences; Volume 23; Issue 22; Pages: 13753
Accession number :
edsair.doi.dedup.....0d07a1b42c63b0bb32942f4b1a48917e
Full Text :
https://doi.org/10.3390/ijms232213753