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Therapeutic potential of novel Cell Division Cycle Kinase 7 inhibitors on TDP-43-related pathogenesis such as Frontotemporal Lobar Degeneration (FTLD) and Amyotrophic Lateral Sclerosis (ALS)

Other TitlesRunning Title: CDC-7 inhibitors correct TDP-43 pathology in ALS and FLTD
AuthorsVaca, Gabriela; Martínez-González, Loreto ; Fernandez, Ana; Rojas-Prats, Elisa; Porras, Gracia ; Cuevas, Eva P. ; Gil, Carmen ; Martínez, Ana ; Martín-Requero, Ángeles
CDC-7 inhibitors
Issue Date17-Jul-2020
PublisherJohn Wiley & Sons
CitationJournal of Neurochemistry (2020)
AbstractTDP-43 has been identified as the major component of protein aggregates found in affected neurons in FTLD-TDP and ALS patients. TDP-43 is hyperphosphorylated,ubiquitinated and cleaved in the C-terminus. CDC-7 was reported to phosphorylate TDP-43. There are not effective treatments for either FTLD-TDP or ALS, being a pressing need the search of new therapies. We hypothesized that modulating CDC-7 activity with small molecules able to interfere with TDP-43 phosphorylation could be a good therapeutic strategy for these diseases. Here, we have studied the effects of novel brain penetrant, thiopurine-based, CDC-7 inhibitors in TDP-43 homeostasis in immortalized lymphocytes from FTLD-TDP patients, carriers of a loss-of-function GRN mutation, as well as in cells derived from sporadic ALS patients. We found that selective CDC-7 inhibitors, ERP1.14a and ERP1.28a are able to decrease the enhanced TDP-43 phosphorylation in cells derived from FTLD-TDP and ALS patients and to prevent cytosolic accumulation of TDP-43. Moreover, treatment of FTLD-TDP lymphoblasts with CDC-7 inhibitors leads to recovering the nuclear function of TDP43-inducing CDK6 repression. We suggest that CDC-7 inhibitors, mainly the heterocyclic compounds here shown, may be considered as promising drugs candidates for the ALS/FTD spectrum.
Description38 p.-7 fig.-2 tab.
Publisher version (URL)https://doi.org/10.1111/jnc.15118
Appears in Collections:(CIB) Artículos
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