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Valproic acid upregulates the expression of the p75NTR/sortilin receptor complex to induce neuronal apoptosis.

ABSTRACT: The antiepileptic and mood stabilizer agent valproic acid (VPA) has been shown to exert anti-tumour effects and to cause neuronal damage in the developing brain through mechanisms not completely understood. In the present study we show that prolonged exposure of SH-SY5Y and LAN-1 human neuroblastoma cells to clinically relevant concentrations of VPA caused a marked induction of the protein and transcript levels of the common neurotrophin receptor p75NTR and its co-receptor sortilin, two promoters of apoptotic cell death in response to proneurotrophins. VPA induction of p75NTR and sortilin was associated with an increase in plasma membrane expression of the receptor proteins and was mimicked by cell treatment with several histone deacetylase (HDAC) inhibitors. VPA and HDAC1 knockdown decreased the level of EZH2, a core component of the polycomb repressive complex 2, and upregulated the transcription factor CASZ1, a positive regulator of p75NTR. CASZ1 knockdown attenuated VPA-induced p75NTR overexpression. Cell treatment with VPA favoured proNGF-induced p75NTR/sortilin interaction and the exposure to proNGF enhanced JNK activation and apoptotic cell death elicited by VPA. Depletion of p75NTR or addition of the sortilin agonist neurotensin to block proNGF/sortilin interaction reduced the apoptotic response to VPA and proNGF. Exposure of mouse cerebellar granule cells to VPA upregulated p75NTR and sortilin and induced apoptosis which was enhanced by proNGF. These results indicate that VPA upregulates p75NTR apoptotic cell signalling through an epigenetic mechanism involving HDAC inhibition and suggest that this effect may contribute to the anti-neuroblastoma and neurotoxic effects of VPA.

SUBMITTER: Dedoni S

PROVIDER: S-EPMC7527367 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Valproic acid upregulates the expression of the p75NTR/sortilin receptor complex to induce neuronal apoptosis.

Dedoni Simona S Marras Luisa L Olianas Maria C MC Ingianni Angela A Onali Pierluigi P

Apoptosis : an international journal on programmed cell death 20201001 9-10

The antiepileptic and mood stabilizer agent valproic acid (VPA) has been shown to exert anti-tumour effects and to cause neuronal damage in the developing brain through mechanisms not completely understood. In the present study we show that prolonged exposure of SH-SY5Y and LAN-1 human neuroblastoma cells to clinically relevant concentrations of VPA caused a marked induction of the protein and transcript levels of the common neurotrophin receptor p75NTR and its co-receptor sortilin, two promoter ...[more]

PMID: 32712736

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Project description:Progranulin (PGRN), a widely secreted growth factor, is involved in multiple biological functions, and mutations located within the PGRN gene (GRN) are a major cause of frontotemporal lobar degeneration with TDP-43-positive inclusions (FLTD-TDP). In light of recent reports suggesting PGRN functions as a protective neurotrophic factor and that sortilin (SORT1) is a neuronal receptor for PGRN, we used a Sort1-deficient (Sort1-/-) murine primary hippocampal neuron model to investigate whether PGRN's neurotrophic effects are dependent on SORT1. We sought to elucidate this relationship to determine what role SORT1, as a regulator of PGRN levels, plays in modulating PGRN's neurotrophic effects.As the first group to evaluate the effect of PGRN loss in Grn knockout primary neuronal cultures, we show neurite outgrowth and branching are significantly decreased in Grn-/- neurons compared to wild-type (WT) neurons. More importantly, we also demonstrate that PGRN overexpression can rescue this phenotype. However, the recovery in outgrowth is not observed following treatment with recombinant PGRN harboring missense mutations p.C139R, p.P248L or p.R432C, indicating that these mutations adversely affect the neurotrophic properties of PGRN. In addition, we also present evidence that cleavage of full-length PGRN into granulin peptides is required for increased neuronal outgrowth, suggesting that the neurotrophic functions of PGRN are contained within certain granulins. To further characterize the mechanism by which PGRN impacts neuronal morphology, we assessed the involvement of SORT1. We demonstrate that PGRN induced-outgrowth occurs in the absence of SORT1 in Sort1-/- cultures.We demonstrate that loss of PGRN impairs proper neurite outgrowth and branching, and that exogenous PGRN alleviates this impairment. Furthermore, we determined that exogenous PGRN induces outgrowth independent of SORT1, suggesting another receptor(s) is involved in PGRN induced neuronal outgrowth.

Dataset Information

Valproic acid upregulates the expression of the p75NTR/sortilin receptor complex to induce neuronal apoptosis.

Publications

Valproic acid upregulates the expression of the p75NTR/sortilin receptor complex to induce neuronal apoptosis.

Similar Datasets

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