Full text

Turn on search term navigation

© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons. Consequent to the loss of these cells, neuromuscular functions decline, causing progressive weakness, muscle wasting, and paralysis, leading to death in 2 to 5 years. More than 90% of ALS cases are sporadic, while the remaining 10% of cases are familial, due to mutations in 40 different genes. One of the most common genes to be mutated in ALS is TARDBP (transactive response DNA binding protein 43), which encodes TDP-43 (TAR DNA-binding protein 43). A mutation in exon 6 of TARDBP causes the aminoacidic substitution G376D in the C-terminal region of TDP-43, leading to its cytoplasmic mislocalization and aggregation. In fibroblasts derived from patients carrying this mutation, we found a strong increase in lysosome number, with overexpression and higher nuclear translocation of the transcription factor TFEB. In contrast, lysosomal functionality was deeply compromised. Interestingly, lysosomal activity was unaffected at an early stage of the disease, worsening in more advanced stages. Moreover, we observed the same pathological phenotype in iPSC (induced pluripotent stem cells)-derived patient motor neurons carrying the G376D mutation. Therefore, this mutation compromises the functionality of lysosomes, possibly contributing to neurodegeneration.

Details

Title
Lysosomal Dysfunction in Amyotrophic Lateral Sclerosis: A Familial Case Linked to the p.G376D TARDBP Mutation
Author
Romano, Roberta 1   VIAFID ORCID Logo  ; Del Fiore, Victoria Stefania 1   VIAFID ORCID Logo  ; Ruotolo, Giorgia 2   VIAFID ORCID Logo  ; Mazzoni, Martina 3 ; Rosati, Jessica 4 ; Conforti, Francesca Luisa 5   VIAFID ORCID Logo  ; Bucci, Cecilia 1   VIAFID ORCID Logo 

 Department of Experimental Medicine, University of Salento, Via Provinciale Lecce-Monteroni n. 165, 73100 Lecce, Italy; [email protected] 
 Cell Reprogramming Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, Viale dei Cappuccini, 71013 San Giovanni Rotondo, Italy; [email protected] (G.R.); [email protected] (M.M.); [email protected] (J.R.); Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy 
 Cell Reprogramming Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, Viale dei Cappuccini, 71013 San Giovanni Rotondo, Italy; [email protected] (G.R.); [email protected] (M.M.); [email protected] (J.R.) 
 Cell Reprogramming Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, Viale dei Cappuccini, 71013 San Giovanni Rotondo, Italy; [email protected] (G.R.); [email protected] (M.M.); [email protected] (J.R.); Departmental Faculty of Medicine, UniCamillus-Saint Camillus International University of Health Sciences, Via di Sant’Alessandro, 8, 00131 Rome, Italy 
 Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy; [email protected] 
First page
2867
Publication year
2025
Publication date
2025
Publisher
MDPI AG
ISSN
16616596
e-ISSN
14220067
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
3188860714
Copyright
© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.