Biology subjects

Zhao, J.-F.

Publications and source records attributed to Zhao, J.-F..

4 recordsLinked to original sources

bioRxiv2026

Targeted dephosphorylation of Tau at the endogenous level promotes its association with microtubules.

Hyperphosphorylation of Tau is a contributory factor for Tauopathies, which constitute a spectrum of neurodegenerative disorders including Alzheimer's disease (AD). Inhibitors of Tau kinases or activators of the Tau phosphatase PP2A to reverse Tau hyperphosphorylation have shown limited therapeutic promise, due primarily to a lack of Tau selectivity. An innovative strategy to potentially circumvent these limitations would be to selectively target the dephosphorylation of phospho-residues on Tau. In this study, we provide evidence for targeted dephosphorylation of phospho-Tau at the endogenous level, including those known to promote Tau aggregation. By recruiting PPP1CA and PPP2CA Affinity-directed (Ad)-Phosphatases to Tau, we demonstrate highly selective targeted dephosphorylation of multiple phospho-residues on Tau in SK-N-MC neuroblastoma cells, leading to its stabilization in microtubules. Moreover, by using a heterobifunctional molecule termed BDPIC (bromoTAG-dTAG proximity-inducing chimera) in cells harbouring bromoTAG and dTAG knockins on Tau and PPP2CA, respectively, we demonstrate highly selective dephosphorylation phospho-residues on Tau.

neuroscience↗

bioRxiv2024

AMPK activation promotes transcriptional activation of TFEB through its dephosphorylation

Transcription Factor EB (TFEB) is a critical regulator of lysosomal biogenesis, autophagy and energy homeostasis through controlling expression of genes belonging to the coordinated lysosomal expression and regulation network. AMP-activated protein kinase (AMPK) has been reported to phosphorylate TFEB at three conserved C-terminal serine residues (S466, S467, S469) and these phosphorylation events were essential for transcriptional activation of TFEB. In sharp contrast to this proposition, here we demonstrate that AMPK activation leads to dephosphorylation of the C-terminal sites, and that AMPK is dispensable for mTORC1-mediated/torin1-sensitive TFEB activation. We show that a synthetic peptide encompassing C-terminal serine residues of TFEB is a poor substrate of AMPK. Treatment of cells with AMPK activator (MK-8722) or mTOR inhibitor (torin1) robustly dephosphorylated TFEB not only at mTORC1-targeted N-terminal serine sites, but also at the C-terminal sites. Loss of function of AMPK abrogated MK-8722-but not torin1-induced dephosphorylation and induction of the vast majority of TFEB target genes.

biochemistry↗

bioRxiv2023

PINK1 regulated basal mitophagy is evident in skeletal muscles

PINK1, mutated in familial forms of Parkinsons disease, initiates mitophagy following mitochondrial depolarization. However, it is difficult to monitor this pathway physiologically in mice as loss of PINK1 does not alter basal mitophagy levels in most tissues. To further characterize this pathway in vivo, we used mito-QC mice in which loss of PINK1 was combined with the mitochondrial-associated POLGD257A mutation. We focused on skeletal muscle as gene expression data indicates that this tissue has the highest PINK1 levels. We found that loss of PINK1 in oxidative hindlimb muscle significantly reduced mitophagy. Of interest, the presence of the POLGD257A mutation, while having a minor effect in most tissues, restored levels of muscle mitophagy caused by the loss of PINK1. Although our observations highlight that multiple mitophagy pathways operate within a single tissue, we identify skeletal muscle as a tissue of choice for the study of PINK1-dependant mitophagy under basal conditions.

cell biology↗

bioRxiv2021

GLUCOCORTICOIDS REGULATE MITOCHONDRIAL FATTY ACID OXIDATION IN FETAL CARDIOMYOCYTES

The late gestational rise in glucocorticoids contributes to the structural and functional maturation of the perinatal heart. Here, we hypothesised that glucocorticoid action contributes to the metabolic switch in perinatal cardiomyocytes from carbohydrate to fatty acid oxidation. In primary mouse fetal cardiomyocytes, dexamethasone treatment induced expression of genes involved in fatty acid oxidation and increased mitochondrial oxidation of palmitate, dependent upon glucocorticoid receptor (GR). Dexamethasone did not, however, induce mitophagy or alter the morphology of the mitochondrial network. In neonatal mice, dexamethasone treatment induced cardiac expression of fatty acid oxidation genes in vivo. However, dexamethasone treatment of pregnant C57Bl/6 mice at embryonic day (E)13.5 or E16.5 failed to induce fatty acid oxidation genes in fetal hearts assessed 24 hours later. Instead, at E17.5, fatty acid oxidation genes were down-regulated by dexamethasone, as was GR itself. PGC-1, required for glucocorticoid-induced maturation of primary mouse fetal cardiomyocytes in vitro, was down-regulated in vivo in fetal hearts at E17.5, 24 hours after dexamethasone administration. Similarly, following a course of antenatal corticosteroids in a sheep model of preterm birth, both GR and PGC-1 were down-regulated in fetal heart. These data suggest endogenous glucocorticoids support the perinatal switch to fatty acid oxidation in cardiomyocytes through changes in gene expression rather than gross changes in mitochondrial volume or mitochondrial turnover. Moreover, our data suggest that treatment with exogenous glucocorticoids may interfere with normal fetal heart maturation, possibly by down-regulating GR. This has implications for clinical use of antenatal corticosteroids when preterm birth is considered a possibility.

physiology↗