Biology subjects

Ulmann, L.

Publications and source records attributed to Ulmann, L..

3 recordsLinked to original sources

bioRxiv2026

ZFP36 is a post-transcriptional regulator of the P2X4 receptor in myeloid cells

P2X4 is an ATP-gated purinergic receptor upregulated in spinal microglia after peripheral nerve injury, where it plays a key role in neuropathic pain. Yet, the molecular mechanisms controlling P2X4 expression remain incompletely understood. To address this question, we examined P2X4 mRNA expression and translation in spinal microglia following nerve injury. While total P2X4 mRNA levels remained unchanged, ribosome-associated P2X4 mRNA increased, revealing a previously unrecognized level of translational regulation. We therefore investigated whether the RNA-binding protein ZFP36 (tristetraprolin), a well-established regulator of inflammatory mRNAs, controls P2X4 expression. Our results demonstrate that the P2X4 3'UTR strongly repressed reporter and protein expression and that ZFP36 emerged as a negative regulator of P2X4 mRNA. This regulation involved phosphorylation-dependent signaling through p38 MAPK and 14-3-3. Moreover, ZFP36 knockdown increased P2X4 protein expression, while manipulation of ZFP36 phosphorylation altered P2X4-dependent ATP-evoked calcium responses. Together, these findings identify ZFP36 as a previously unrecognized post-transcriptional regulator of P2X4, extending its role beyond inflammatory mediators to a functional purinergic receptor. They reveal post-transcriptional control of receptor availability as a novel regulatory layer linking myeloid cell state to purinergic responsiveness and provide a new framework for understanding microglial P2X4 regulation in neuropathic pain.

neuroscience↗

bioRxiv2022

Microglial P2X4 receptors promote ApoE degradation and cognitive deficits in Alzheimer disease

Numerous evidence support that microglia contributes to the progression of Alzheimers disease. P2X4 receptors are ATP-gated channels, which are de novo expressed in a subset of reactive microglia associated to various pathological contexts, contributing to microglial functions. Here, we investigated the role of P2X4 in the context of Alzheimer disease (AD). In both human AD brain and APPswe/PSEN1dE9 mice, P2X4 is almost exclusively expressed in plaque associated microglia. Genetic deletion of P2rx4 results in the reversal of cognitive declines and in a lower amount of soluble A{beta}1 -42 in 12 months old APP/PS1 mice, while no obvious alteration of plaque associated microglia characteristics is observed. Using proteomic, we identified ApoE as a specific P2X4 interacting protein. We found that P2X4 regulates lysosomal cathepsin B activity promoting ApoE degradation; P2rx4 deletion results in higher amount of intracellular and secreted ApoE in both BMDM and microglia from APP/PS1 brain. Our results support that microglial P2X4 promotes lysosomal ApoE degradation, indirectly altering A{beta} peptide clearance, which in turn might promote synaptic dysfunctions and cognitive deficits. Our findings also uncover a specific interplay between purinergic signaling, microglial ApoE, sA{beta} species and cognitive deficits associated with AD.

neuroscience↗

bioRxiv2020

A P2rx7 passenger mutation affects the vitality and function of immune cells in P2X4ko and other transgenic mice

Among laboratory mouse strains many genes are differentially expressed in the same cell population. As consequence, gene targeting in 129-derived embryonic stem cells (ESCs) and backcrossing the modified mice onto the C57BL/6 (B6) background can introduce passenger mutations in the close proximity of the targeted gene. Here, we demonstrate that several 129-originating transgenic mice in which P2rx7-neighboring genes were targeted carry a P2rx7 passenger mutation that affects the vitality and function of T cells. By the example of P2rx4tm1Rass we demonstrate that CD4+ and CD8+ T cells derived from these mice express higher levels of P2X7 when compared to corresponding cell populations in B6-WT mice. The increased T cell sensitivity towards the P2X7 activators adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide (NAD+) rendered these cells more vulnerable towards NAD-induced cell death (NICD) compared to their B6-WT counterparts. The enhanced NICD sensitivity significantly affected the outcome of functional assays e.g. cytokine production and cell migration. For P2rx4tm1Rass, we demonstrate that the expression of P2X7 is diminished in several innate immune cell populations, possibly as a side effect of P2rx4 targeting, and independent of the P2rx7 passenger mutation. These results need to be considered when working with P2rx4tm1Rass mice or other 129-based transgenic strains that target P2rx7 neighboring genes and might have implications for other mouse models.

immunology↗