Title |
Targeting TDP-43 phosphorylation by Casein Kinase-1δ inhibitors: a novel strategy for the treatment of frontotemporal dementia
|
---|---|
Published in |
Molecular Neurodegeneration, April 2016
|
DOI | 10.1186/s13024-016-0102-7 |
Pubmed ID | |
Authors |
Carolina Alquezar, Irene G. Salado, Ana de la Encarnación, Daniel I. Pérez, Fermín Moreno, Carmen Gil, Adolfo López de Munain, Ana Martínez, Ángeles Martín-Requero |
Abstract |
Mutations in the progranulin gene (GRN) are the most common cause of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). TDP-43 pathology is characterized by the hyperphosphorylation of the protein at Serine 409/410 residues. Casein kinase-1δ (CK-1δ) was reported to phosphorylate TDP-43 directly. Previous works from our laboratory described the presence of CDK6/pRb-dependent cell cycle alterations, and cytosolic accumulation of TDP-43 protein in lymphoblast from FTLD-TDP patients carriers of a loss-of function mutation in GRN gene (c.709-1G > A). In this work, we have investigated the effects of two brain penetrant CK-1δ inhibitors (IGS-2.7 and IGS-3.27) designed and synthetized in our laboratory on cell proliferation, TDP-43 phosphorylation and subcellular localization, as well as their effects on the known nuclear TDP-43 function repressing the expression of CDK6. We report here that both CK-1δ inhibitors (IGS-2.7 and IGS-3.27) normalized the proliferative activity of PGRN-deficient lymphoblasts by preventing the phosphorylation of TDP-43 fragments, its nucleo-cytosol translocation and the overactivation of the CDK6/pRb cascade. Moreover, ours results show neuroprotective effects of CK-1δ inhibitors in a neuronal cell model of induced TDP-43 phosphorylation. Our results suggest that modulating CK-1δ activity could be considered a novel therapeutic approach for the treatment of FTLD-TDP and other TDP-43 proteinopathies. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 1 | 50% |
Unknown | 1 | 50% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 2 | 100% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 81 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 18 | 22% |
Researcher | 9 | 11% |
Student > Bachelor | 8 | 10% |
Student > Master | 6 | 7% |
Student > Postgraduate | 5 | 6% |
Other | 10 | 12% |
Unknown | 25 | 31% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 19 | 23% |
Neuroscience | 12 | 15% |
Agricultural and Biological Sciences | 6 | 7% |
Pharmacology, Toxicology and Pharmaceutical Science | 4 | 5% |
Chemistry | 3 | 4% |
Other | 9 | 11% |
Unknown | 28 | 35% |