Recapitulation of Pathological TDP-43 Features in Immortalized Lymphocytes from Sporadic ALS Patients

Molecular Neurobiology
Diana PosaÁngeles Martín-Requero

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disorder of still unknown etiology that results in loss of motoneurons, paralysis, and death, usually between 2 and 4 years from onset. There are no currently available ALS biomarkers to support early diagnosis and to facilitate the assessment of the efficacy of new treatments. Since ALS is considered a multisystemic disease, here we have investigated the usefulness of immortalized lymphocytes from sporadic ALS patients to study TDP-43 homeostasis as well as to provide a convenient platform to evaluate TDP-43 phosphorylation as a novel therapeutic approach for ALS. We report here that lymphoblasts from ALS patients recapitulate the hallmarks of TDP-43 processing in affected motoneurons, such as increased phosphorylation, truncation, and mislocalization of TDP-43. Moreover, modulation of TDP-43 by an in-house designed protein casein kinase-1δ (CK-1δ) inhibitor, IGS3.27, reduced phosphorylation of TDP-43, and normalized the nucleo-cytosol translocation of TDP-43 in ALS lymphoblasts. Therefore, we conclude that lymphoblasts, easily accessible cells, from ALS patients could be a useful model to study pathological features of ALS disease and a suitable plat...Continue Reading

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Citations

May 30, 2020·British Journal of Pharmacology·Emanuele Buratti
Aug 2, 2020·British Journal of Pharmacology·Valle PalomoAna Martinez
Apr 4, 2021·International Journal of Molecular Sciences·Isabel Lastres-BeckerÁngeles Martin-Requero
Feb 21, 2019·ACS Chemical Neuroscience·Valle PalomoAna Martinez
Aug 28, 2021·International Journal of Molecular Sciences·Loreto Martínez-GonzálezAna Martínez
Nov 18, 2021·Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration
Jan 6, 2022·Journal of Medicinal Chemistry·Olmo Martín-CámaraJ Carlos Menéndez
Jan 23, 2022·Clinical and Translational Medicine·Georgios PampalakisGeorgia Sotiropoulou

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Methods Mentioned

BETA
confocal microscopy
Protein Assay
electrophoresis

Software Mentioned

Graph Pad Prism
Image Studio Lite
Volocity

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