Increasing progranulin levels and blockade of the ERK1/2 pathway: Upstream and downstream strategies for the treatment of progranulin deficient frontotemporal dementia

Alquézar, Carolina; Esteras, Noemí; Encarnación, Ana de la; Moreno, Fermín; Munáin, Adolfo López de; Martín-Requero, Ángeles

doi:10.1016/j.euroneuro.2014.12.007

Cited by 22 publications

(25 citation statements)

References 86 publications

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“…Together these observations demonstrate that peripheral cells from ALS patients recapitulate the increased phosphorylation and subcellular mislocalization of TDP-43 that characterizes the altered motor neurons of ALS patients [19][20][21]. On the other hand, the results presented herein are in accordance with previous reports from this laboratory showing alterations in TDP-43 phosphorylation and in TDP-43 translocation from the nucleus to cytosol in lymphoblasts of FTLD-TDP patients [37,40,41]. These observations give further support to the idea of an ALS-FTLD continuum [42,43].…”

Section: Discussionsupporting

confidence: 92%

Recapitulation of Pathological TDP-43 Features in Immortalized Lymphocytes from Sporadic ALS Patients

et al. 2018

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Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disorder of still unknown etiology that results in loss of motoneurons, paralysis, and death, usually between 2 and 4 years from onset. There are no currently available ALS biomarkers to support early diagnosis and to facilitate the assessment of the efficacy of new treatments. Since ALS is considered a multisystemic disease, here we have investigated the usefulness of immortalized lymphocytes from sporadic ALS patients to study TDP-43 homeostasis as well as to provide a convenient platform to evaluate TDP-43 phosphorylation as a novel therapeutic approach for ALS. We report here that lymphoblasts from ALS patients recapitulate the hallmarks of TDP-43 processing in affected motoneurons, such as increased phosphorylation, truncation, and mislocalization of TDP-43. Moreover, modulation of TDP-43 by an in-house designed protein casein kinase-1δ (CK-1δ) inhibitor, IGS3.27, reduced phosphorylation of TDP-43, and normalized the nucleo-cytosol translocation of TDP-43 in ALS lymphoblasts. Therefore, we conclude that lymphoblasts, easily accessible cells, from ALS patients could be a useful model to study pathological features of ALS disease and a suitable platform to test the effects of potential disease-modifying drugs even in a personalized manner.

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Section: Discussionsupporting

confidence: 92%

Recapitulation of Pathological TDP-43 Features in Immortalized Lymphocytes from Sporadic ALS Patients

et al. 2018

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“…Previous work from this laboratory demonstrated that lymphoblasts derived from carriers of a loss-of-function GRN mutation (c.709-1G > A), asymptomatic or FTLD patients, show higher proliferative activity compared with control lymphoblasts, that is associated with increased levels of CDK6 protein [ 21 , 22 ]. In addition, these lymphoblastoid cell lines display enhanced accumulation of cytosolic TDP-43, a hallmark of FTLD-TDP disease [ 22 , 30 ]. The TDP-43 protein present in the brain deposits in FTLD-TDP patients is highly phosphorylated [ 8 ], being CK-1δ kinase involved in phosphorylation of the molecule [ 13 , 19 ].…”

Section: Resultsmentioning

confidence: 99%

“…Since it has been suggested that phosphorylation of TDP-43 may disrupt the balance between cytosolic and nuclear TDP-43 localization, we were interested in elucidating whether these CK-1δ inhibitors were able to normalize the cytosolic TDP-43 accumulation, characteristic of PGRN-deficient lymphoblasts [ 22 , 30 ]. To this end, we carried out fractionation of cell extracts after the treatment with the corresponding CK-1δ inhibitor, and processed them for Western blotting with an anti-TDP-43 antibody.…”

Section: Resultsmentioning

confidence: 99%

“…The re-entry of quiescent neurons into the cell cycle may result in a mitotic failure and cell death [ 27 – 29 ]. Moreover, we found accumulated TDP-43 in the cytoplasm of these PGRN-deficient lymphoblasts [ 21 , 30 ]. Therefore, it appears that these cell lines from patients, easily accessible, could represent a suitable platform to search novel disease-modifying drugs.…”

Section: Introductionmentioning

confidence: 99%

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

Alquézar

Salado

Encarnación

et al. 2016

Mol Neurodegeneration

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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.

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“…HDAC inhibitors in particular the multi-HDAC targeting compound SAHA (Vorinostat), have been shown previously to increase GRN transcription in a mouse Neuro-2A reporter cell line, human lymphoblastoid cell lines from a healthy control and an FTD subject with a nonsense GRN mutation, and in human SH-SY5Y neuroblastoma cells (Cenik et al, 2011, FORUM Pharmaceuticals Inc, 2015, Alquezar et al, 2015). Crebinostat, another potent, multi-HDAC targeting compound, has also been shown to enhance Grn mRNA expression in mouse cortical neurons (Fass et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Selectivity and Kinetic Requirements of HDAC Inhibitors as Progranulin Enhancers for Treating Frontotemporal Dementia

She

Kurtser

Reis

et al. 2017

Cell Chemical Biology

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Summary Frontotemporal dementia (FTD) arises from neurodegeneration in the frontal, insular, and anterior temporal lobes. Autosomal dominant causes of FTD include heterozygous mutations in the GRN gene causing haploinsufficiency of progranulin (PGRN) protein. Recently, histone deacetylase (HDAC) inhibitors have been identified as enhancers of PGRN expression, although the mechanisms through which GRN is epigenetically regulated remain poorly understood. Using a chemogenomic toolkit, including optoepigenetic probes, we show that inhibition of Class I HDACs is sufficient to upregulate PGRN in human neurons and only inhibitors with apparent fast binding to their target HDAC complexes are capable of enhancing PGRN expression. Moreover, we identify regions in the GRN promoter in which elevated H3K27 acetylation and transcription factor EB (TFEB) occupancy correlate with HDAC-inhibitor mediated upregulation of PGRN. These findings have implications for epigenetic and cis-regulatory mechanisms controlling human GRN expression and may advance translational efforts to develop targeted therapeutics for treating PGRN-deficient FTD.

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Increasing progranulin levels and blockade of the ERK1/2 pathway: Upstream and downstream strategies for the treatment of progranulin deficient frontotemporal dementia

Cited by 22 publications

References 86 publications

Recapitulation of Pathological TDP-43 Features in Immortalized Lymphocytes from Sporadic ALS Patients

Recapitulation of Pathological TDP-43 Features in Immortalized Lymphocytes from Sporadic ALS Patients

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

Selectivity and Kinetic Requirements of HDAC Inhibitors as Progranulin Enhancers for Treating Frontotemporal Dementia

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