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Abstract: Background: Dermic fibroblasts have been proposed as a potential genetic-ALS cellular model. This study aimed to explore whether dermic fibroblasts from patients with sporadic-ALS (sALS) recapitulate alterations typical of ALS motor neurons and exhibit abnormal DNA-damage response.
Methods: Dermic fibroblasts were obtained from eight sALS patients and four control subjects. Cellular characterization included proliferation rate analysis, cytoarchitecture studies and confocal immunofluorescence assessment for TDP-43. Additionally, basal and irradiation-induced DNA damage was evaluated by confocal immunofluorescence and biochemical techniques.
Results: sALS-fibroblasts showed decreased proliferation rates compared to controls. Additionally, whereas control fibroblasts exhibited the expected normal spindle-shaped morphology, ALS fibroblasts were thinner, with reduced cell size and enlarged nucleoli, with frequent cytoplasmic TDP-43aggregates. Also, baseline signs of DNA damage were evidenced more frequently in ALS-derived fibroblasts (11 versus 4% in control-fibroblasts). Assays for evaluating the irradiation-induced DNA damage demonstrated that DNA repair was defective in ALS-fibroblasts, accumulating more than double of ?H2AX-positive DNA damage foci than controls. Very intriguingly, the proportion of fibroblasts particularly vulnerable to irradiation (with more than 15 DNA damage foci per nucleus) was seven times higher in ALS-derived fibroblasts than in controls.
Conclusions: Dermic-derived ALS fibroblasts recapitulate relevant cellular features of sALS and show a higher susceptibility to DNA damage and defective DNA repair responses. Altogether, these results support that dermic fibroblasts may represent a convenient and accessible ALS cellular model to study pathogenetic mechanisms, particularly those related to DNA damage response, as well as the eventual response to disease-modifying therapies.
Fuente: J Neurol
. 2020 May;267(5):1291-1299
Año de publicación: 2020
Nº de páginas: 9
Tipo de publicación: Artículo de Revista
Url de la publicación: https://doi.org/10.1007/s00415-020-09704-8
JAVIER RIANCHO ZARRABEITIA
CASTANEDO VÁZQUEZ, DAVID
GIL BEA, FRANCISCO
OLGA TAPIA MARTINEZ
JANA AROZAMENA GARCIA
DURÁN VÍAN, CARLOS
SEDANO, MARÍA JOSÉ
MARIA TERESA BERCIANO BLANCO
LOPEZ DE MUNAIN, ADOLFO
MIGUEL ANGEL LAFARGA COSCOJUELA