Targeting TDP-43 phosphorylation by Casein Kinase-1δ inhibitors: a novel strategy for the treatment of frontotemporal dementia

Abstract

BackgroundMutations 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.ResultsWe 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.ConclusionsOur 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.

Motor neuron preservation and decrease of in vivo TDP-43 phosphorylation by protein CK-1δ kinase inhibitor treatment

“…Effect of IGS-2.7 on TDP-43 phosphorylation of lymphoblasts from control and sporadic ALS individuals. Previous work from our laboratory demonstrated that lymphoblasts derived from FTD and ALS www.nature.com/scientificreports www.nature.com/scientificreports/ patients, easily available, could represent a suitable platform to search novel disease-modifying drugs 16,17 . For this reason, we decided to explore the biological profile of IGS-2.7 on lymphoblasts derived from sALS patients.…”

Endoplasmic Reticulum Stress Signalling Induces Casein Kinase 1-Dependent Formation of Cytosolic TDP-43 Inclusions in Motor Neuron-Like Cells

“…Our data show that CK1 plays a vital role in TDP-43 cytoplasmic inclusion formation under conditions of chronic ER stress. A role for CK1 is supported in previously published reports [22,26,27], which has relevance for the pharmacological targeting of TDP-43 aggregation [14,27,28,30].…”

“…TDP-43 is a substrate for a number of protein kinasescasein kinase 1 (CK1) has been identified as a direct TDP-43 kinase, including at S409/410 [21][22][23][24][25], and its overexpression can induce TDP-43 phosphorylation [26]. Furthermore, custom synthesized CK1δ inhibitors were able to reduce TDP-43 phosphorylation and protect cultured cells against ethacrynic acid challenge, which induces neuroblastoma cell death by mediating the phosphorylation of TDP-43 [27]. In addition, there has been substantial interest in developing CK1 inhibitors for MND [28][29][30].…”

Targeting Protein Kinase CK1δ with Riluzole: Could It Be One of the Possible Missing Bricks to Interpret Its Effect in the Treatment of ALS from a Molecular Point of View?

“…EAAT2 is normally expressed in glial cells, and it is responsible in synaptic boutons for almost 90 % of glutamate reuptake, thereby preventing its accumulation and toxicity. CK1δ inhibitors are able to restore the correct nuclear localization of TDP‐43, and thus riluzole itself modulating CK1δ activity could ensure the physiological processing and maturation of specific mRNA transcripts, mediated by TDP‐43 . This hypothesis found an experimental confirmation in two independent studies: in the first, riluzole showed the ability to reverse cocaine‐induced suppression of the glutamate transporter EAAT2 in the nucleus accumbens (NAc), and coherently, in the second study, long‐term riluzole administration rescued EAAT2 mRNA levels and protein expression in the hippocampus .…”