Targeting nuclear protein TDP-43 by cell division cycle kinase 7 inhibitors: A new therapeutic approach for amyotrophic lateral sclerosis

Rojas-Prats, Elisa; Martínez-González, Loreto; Gonzalo‐Consuegra, Claudia; Liachko, Nicole F.; Pérez, Concepción; Ramírez, David; Kraemer, Brian C.; Martín-Requero, Ángeles; Pérez, Daniel I.; Gil, Carmen; Lago, Eva de; Martı́nez, Ana

doi:10.1016/j.ejmech.2020.112968

Cited by 35 publications

(24 citation statements)

References 52 publications

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“…WNT signaling is typically implicated in cell growth, proliferation, and specification ( Clevers, 2006 ). Previous studies have observed an upregulation in the cell cycle in ALS MNs and inhibition of CDKs improve disease phenotypes ( Bhinge et al., 2017 ; Rojas-Prats et al., 2021 ; Ranganathan and Bowser, 2010 ). An attractive possibility is that cell-cycle reactivation through aberrant WNT signaling contributes to MN death ( Frade and Ovejero-Benito, 2015 ; Bryja et al., 2017 ).…”

Section: Discussionmentioning

confidence: 91%

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Upregulation of β-catenin due to loss of miR-139 contributes to motor neuron death in amyotrophic lateral sclerosis

et al. 2022

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Section: Discussionmentioning

confidence: 91%

“…It is possible that some CDKs have a critical cell-cycle-independent role to play in MN homeostasis. In this case, targeting specific CDKs may improve ALS MN survival as observed in SMA ( Hor et al., 2018 ) and TDP43 mutant mice ( Rojas-Prats et al., 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Upregulation of β-catenin due to loss of miR-139 contributes to motor neuron death in amyotrophic lateral sclerosis

et al. 2022

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“…Cell division cycle kinase 7 (CDC7) plays a role in the hyperphosphorylation of TDP-43, a central protein in the pathogenesis of ALS [43]. Notably, CDC7 inhibitors have shown promise in ALS animal and cellular models by reducing TDP43 phosphorylation [44,45]. Furthermore, a small molecule inhibitor of CDC7 reduced TDP-43 phosphorylation and prevented neurodegeneration in TDP-43-transgenic animals [43].…”

Section: Biological and Functional Analyses Of Switch Genesmentioning

confidence: 99%

Network Analysis Identifies Sex-Specific Gene Expression Changes in Blood of Amyotrophic Lateral Sclerosis Patients

Santiago¹,

Quinn

Potashkin

2021

IJMS

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Understanding the molecular mechanisms underlying the pathogenesis of amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease, is a major challenge. We used co-expression networks implemented by the SWitch Miner software to identify switch genes associated with drastic transcriptomic changes in the blood of ALS patients. Functional analyses revealed that switch genes were enriched in pathways related to the cell cycle, hepatitis C, and small cell lung cancer. Analysis of switch genes by sex revealed that switch genes from males were associated with metabolic pathways, including PI3K-AKT, sphingolipid, carbon metabolism, FOXO, and AMPK signaling. In contrast, female switch genes related to infectious diseases, inflammation, apoptosis, and atherosclerosis. Furthermore, eight switch genes showed sex-specific gene expression patterns. Collectively, we identified essential genes and pathways that may explain sex differences observed in ALS. Future studies investigating the potential role of these genes in driving disease disparities between males and females with ALS are warranted.

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“…All of them are predicted to cross the human brain–blood barrier using a parallel artificial membrane permeability assay methodology. The compounds are able to protect the cell line SH‐SY5Y from the death caused by the increase of TDP‐43 pathology (Rojas‐Prats et al, Submitted). Here we report the effects of some of these compounds in rescuing TDP‐43 homeostasis in immortalized lymphocytes from FTLD‐TDP (Alquezar et al., 2016) or ALS patients (Posa et al., 2019).…”

Section: Introductionmentioning

confidence: 99%

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)

Vaca

Martínez-González

Fernandez

et al. 2020

Journal of Neurochemistry

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TDP‐43 has been identified as the major component of protein aggregates found in affected neurons in FTLD‐TDP and amyotrophic lateral sclerosis (ALS) patients. TDP‐43 is hyperphosphorylated, ubiquitinated, and cleaved in the C‐terminus. CDC‐7 was reported to phosphorylate TDP‐43. There are no effective treatments for either FTLD‐TDP or ALS, being a pressing need for the search of new therapies. We hypothesized that modulating CDC‐7 activity with small molecules that are 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 TDP‐43‐inducing CDK6 repression. We suggest that CDC‐7 inhibitors, mainly the heterocyclic compounds here shown, may be considered as promising drug candidates for the ALS/FTD spectrum.

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Targeting nuclear protein TDP-43 by cell division cycle kinase 7 inhibitors: A new therapeutic approach for amyotrophic lateral sclerosis

Cited by 35 publications

References 52 publications

Upregulation of β-catenin due to loss of miR-139 contributes to motor neuron death in amyotrophic lateral sclerosis

Upregulation of β-catenin due to loss of miR-139 contributes to motor neuron death in amyotrophic lateral sclerosis

Network Analysis Identifies Sex-Specific Gene Expression Changes in Blood of Amyotrophic Lateral Sclerosis Patients

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)

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