CDC7 inhibition blocks pathological TDP‐43 phosphorylation and neurodegeneration

Liachko, Nicole F.; McMillan, Pamela J.; Guthrie, Chris R.; Bird, Thomas D.; Leverenz, James B.; Kraemer, Brian C.

doi:10.1002/ana.23870

Cited by 108 publications

(110 citation statements)

References 62 publications

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“…2a-e), consistent with a conserved role for calcineurin as a TDP-43 phosphatase. We and others have observed a link between total TDP-43 and pTDP levels; when pTDP is increased, total TDP-43 protein also increases [7, 26, 33, 62]. This may be due to changes in protein stability or pTDP’s blockade of normal TDP-43 protein degradation pathways.…”

Section: Resultsmentioning

confidence: 90%

“…Phosphorylated TDP-43 was prepared by in vitro phosphorylation using recombinant CDC7 kinase and glutathione-bound GST-TDP-43 fusion protein as previously described [33]. Dephosphorylation was carried out in dephosphorylation reaction buffer [50 mm HEPES, pH 7.2, 50 mM NaCl, 2 mM MnCl 2 , 1 mM CaCl 2 , 1 mM DTT].…”

Section: Methodsmentioning

confidence: 99%

“…These pathological phosphorylation sites cluster in the C-terminus of the TDP-43 protein, predominantly at serines 409 and 410 (S409/410), although phosphorylation at S379, S403, and S404 also correlate with disease pathology [18, 45]. Phosphorylation at S409/410 has been shown to promote decreased TDP-43 protein turnover, increased TDP-43 stabilization, cellular mislocalization of TDP-43, protein aggregation, and neurodegeneration [3, 7, 18, 32, 33, 62]. …”

Section: Introductionmentioning

confidence: 99%

“…Several kinases have been identified that phosphorylate TDP-43, including CK1/2, CDC7, and TTBK1/2 [18, 33, 34]. These kinases may act in response to overlapping or unique sets of cellular or environmental triggers.…”

Section: Introductionmentioning

confidence: 99%

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The phosphatase calcineurin regulates pathological TDP-43 phosphorylation

et al. 2016

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Detergent insoluble inclusions of TDP-43 protein are hallmarks of the neuropathology in over 90% of amyotrophic lateral sclerosis (ALS) cases and approximately half of frontotemporal dementia (FTLD-TDP) cases. In TDP-43 proteinopathy disorders, lesions containing aggregated TDP-43 protein are extensively post-translationally modified, with phosphorylated TDP-43 (pTDP) being the most consistent and robust marker of pathological TDP-43 deposition. Abnormally phosphorylated TDP-43 has been hypothesized to mediate TDP-43 toxicity in many neurodegenerative disease models. To date several different kinases have been implicated in the genesis of pTDP, but no phosphatases have been shown to reverse pathological TDP-43 phosphorylation. We have identified the phosphatase calcineurin as an enzyme binding to and catalyzing the removal of pathological C-terminal phosphorylation of TDP-43 in vitro. In C. elegans models of TDP-43 proteinopathy, genetic elimination of calcineurin results in accumulation of excess pTDP, exacerbated motor dysfunction, and accelerated neurodegenerative changes. In cultured human cells, treatment with FK506 (tacrolimus), a calcineurin inhibitor, results in accumulation of pTDP species. Lastly, calcineurin co-localizes with pTDP in degenerating areas of the central nervous system in subjects with FTLD-TDP and ALS. Taken together these findings suggest calcineurin acts on pTDP as a phosphatase in neurons. Furthermore, patient treatment with calcineurin inhibitors may have unappreciated adverse neuropathological consequences.

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Section: Resultsmentioning

confidence: 90%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The phosphatase calcineurin regulates pathological TDP-43 phosphorylation

et al. 2016

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“…Alternatively, it is possible that the modest reduction in TDP-43 expression is not responsible for the suppression in toxicity seen with Hat-trick mutants. Given the putative role of Hat-trick in chromatin modeling, it is tempting to speculate that loss of Hat-trick may prevent cell-cycle re-entry, a mechanism that has been linked to ALS pathogenesis [42] and, specifically, TDP-43 toxicity [38, 43]. Indeed, mutations in genes encoding other chromatin regulators are over-represented in ALS [7].…”

Section: Resultsmentioning

confidence: 99%

Age-Dependent TDP-43-Mediated Motor Neuron Degeneration Requires GSK3, hat-trick, and xmas-2

et al. 2015

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Summary The RNA processing protein TDP-43 is central to the pathogenesis of amyotrophic lateral sclerosis (ALS), the most common adult-onset motor neuron (MN) disease [1–4]. TDP-43 is conserved in Drosophila, where it has been the topic of considerable study, but how TDP-43 mutations lead to age-dependent neurodegeneration is unclear and most approaches have not directly examined changes in MN morphology with age [5]. We used a mosaic approach to study age-dependent MN loss in the adult fly leg where it is possible to resolve single motor axons, NMJs and active zones, and perform rapid forward genetic screens. We show that expression of TDP-43Q331K caused dying-back of NMJs and axons, which could not be suppressed by mutations that block Wallerian degeneration. We report the identification of three genes that suppress TDP-43 toxicity, including Shaggy/GSK3, a known modifier of neurodegeneration [6]. The two additional novel suppressors, Hat-trick and Xmas-2, function in chromatin modeling and RNA export, two processes recently implicated in human ALS [7, 8]. Loss of Shaggy/GSK3, Hat-trick or Xmas-2 does not suppress Wallerian degeneration, arguing TDP-43Q331K-induced and Wallerian degeneration are genetically distinct processes. In addition to delineating genetic factors that modify TDP-43 toxicity, these results establish the Drosophila adult leg as a valuable new tool for the in vivo study of adult MN phenotypes.

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A chemogenomic approach is required for effective treatment of amyotrophic lateral sclerosis

Pampalakis

Angelis

Zingkou

et al. 2022

Clinical & Translational Med

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ALS is a fatal untreatable disease involving degeneration of motor neurons. Μultiple causative genes encoding proteins with versatile functions have been identified indicating that diverse biological pathways lead to ALS. Chemical entities still represent a promising choice to delay ALS progression, attenuate symptoms and/or increase life expectancy, but also gene‐based and stem cell‐based therapies are in the process of development, and some are tested in clinical trials. Various compounds proved effective in transgenic models overexpressing distinct ALS causative genes unfortunately though, they showed no efficacy in clinical trials. Notably, while animal models provide a uniform genetic background for preclinical testing, ALS patients are not stratified, and the distinct genetic forms of ALS are treated as one group, which could explain the observed discrepancies between treating genetically homogeneous mice and quite heterogeneous patient cohorts. We suggest that chemical entity‐genotype correlation should be exploited to guide patient stratification for pharmacotherapy, that is administered drugs should be selected based on the ALS genetic background.

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CDC7 inhibition blocks pathological TDP‐43 phosphorylation and neurodegeneration

Cited by 108 publications

References 62 publications

The phosphatase calcineurin regulates pathological TDP-43 phosphorylation

The phosphatase calcineurin regulates pathological TDP-43 phosphorylation

Age-Dependent TDP-43-Mediated Motor Neuron Degeneration Requires GSK3, hat-trick, and xmas-2

A chemogenomic approach is required for effective treatment of amyotrophic lateral sclerosis

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