Biology subjects

Tu, C.-L.

Publications and source records attributed to Tu, C.-L..

4 recordsLinked to original sources

bioRxiv2025

Extracellular Ca2+-Sensing Receptor (CaSR) Regulates Hypothalamic Function to Control Energy and Skeletal Metabolism in Mice

Introductory paragraphThe extracellular Calcium-sensing receptor (CaSR) regulates cellular responsiveness to physiological changes in ionized calcium (Ca2+) concentrations. The CaSR is expressed in the brain, including in hypothalamic growth hormone stimulating GHRH and anorectic POMC neurons that control growth and energy homeostasis. We embryonically deleted the Casr gene in neurons to create NeuronCaSR-/- mice to delineate the role of this receptor in regulating growth, skeletal development, and energy metabolism. NeuronCaSR-/- mice had reduced size, weight and bone mass compared to littermate controls, with a dysregulated growth hormone axis. They also showed increased adiposity and circulating leptin levels, leptin resistance, and decreased glucose tolerance, along with reduced expression of the anorectic precursor peptide POMC and secondary increases in the expression of the anorectic peptide AgRP in the hypothalamus of NeuronCaSR-/- mice. Knockdown of CaSR in adult mice specifically in the hypothalamic arcuate nucleus, where GHRH, POMC and AgRP neurons reside, also resulted in increased body weight, adiposity, leptin resistance, and glucose intolerance, and reduced bone mass. Together these data suggest that neuronal CaSR critically regulates energy and skeletal metabolism and body growth by modulating hypothalamic function, representing a new paradigm for central integration of calcaemic activities with body function.

physiology↗

bioRxiv2025

Transcriptional and neuroprotective effects of hexokinase-2 inhibitors administered afterstroke

The inflammatory response induced by stroke can exacerbate injury to peri-infarct tissue. Microglia and other immune cells that mediate this response require increased glycolytic flux during pro-inflammatory activation. These cells, unlike neurons and most other cell types, utilize hexokinase-2 (HK2) rather than hexokinase-1 for glycolysis, such that HK2 inhibitors may selectively target them to suppress post-ischemic inflammation. Here we compared the effects of the non-selective hexokinase inhibitor 2-deoxyglucose to the HK2-selective inhibitors lonidamine and 3-bromopyruvate on secondary injury after stroke. A spatial transcriptomic assessment was performed in parallel to compare effects of the inhibitors on microglial gene expression and microglia - neuron interactions and to screen for off-target effects. Each of the inhibitors suppressed pro-inflammatory gene upregulation in peri-infarct microglia and attenuated the upregulation of cell stress functional pathways in the neighboring neurons, but had minimal effect on neuronal gene expression in uninjured cortex. The HK2-selective inhibitors were more effective than 2-deoxyglucose in suppressing morphological microglial changes, neuronal oxidative stress, and neurite loss. 3-bromopyruvate administered after stroke produced long-term improvements in functional outcome. Selective HK2 inhibitors may thus provide a clinically applicable means to suppress microglial activation and thereby improve outcomes after stroke without endangering neuronal energy metabolism.

neuroscience↗

bioRxiv2024

Spatially conserved pathoprotein profiling in the human suprachiasmatic nucleus in progressive Alzheimer disease stages

Individuals with Alzheimers Disease (AD) experience circadian rhythm disorder. The circadian rhythm is synchronized by a master clock, the suprachiasmatic nucleus (SCN), which is a tiny hypothalamic nucleus. Little is known about the molecular and pathological changes that occur in the SCN during AD progression. We examined postmortem brains of 12 controls without AD neuropathological changes (Braak stage 0) and 36 subjects at progressive Braak stages (I, II, and VI). To investigate potential AD-specific changes, we measured the neuronal counts of arginine vasopressin (AVP) and vasoactive intestinal peptide (VIP) positive neurons, along with the Braak stages in the SCN. We investigated in adjacent hypothalamic nuclei which are also composed of AVP+ neurons but show more resilience to AD: paraventricular nucleus (PVN) and supraoptic nucleus (SON). To understand the dysregulated proteins associated to AD progression, we performed in-situ proteomics, investigating 57 proteins, including commonly dysregulated in AD, using GeoMx Digital Spatial Profiling (DSP) in the three nuclei (total of 703 area of interests). Neurofibrillary tangles (NFTs) and tau fibrils were found selectively in SCN. We failed to detect NFTs in SON, only a mild dysregulation of p-tau at Braak VI in PVN and SON. Amyloid plaque was absent in the SCN and SON. Additionally, the SCN showed increased glial proteins already at Braak stage I, whereas the level of these proteins sustained in the other nuclei. The SCN is exclusively vulnerable to AD-tau pathology and show immune dysregulation even at Braak I but is protected against amyloid plaque. This finding revealed selectively in amnestic AD, showing more resilience in AD variant. This tau-related molecular dysregulation in the SCN contributes to circadian rhythm disturbances in AD, a phenomenon observed before the onset of cognitive disorder.

neuroscience↗

bioRxiv2023

Structure-based discovery of positive allosteric modulators for the calcium sensing receptor

Drugs acting as positive allosteric modulators (PAMs) to enhance the activation of the calcium sensing receptor (CaSR) and to suppress parathyroid hormone (PTH) secretion can treat hyperparathyroidism but suffer from side effects including hypocalcemia and arrhythmias. Seeking new CaSR modulators, we docked libraries of 2.7 million and 1.2 billion molecules against transforming pockets in the active-state receptor dimer structure. Consistent with simulations suggesting that docking improves with library size, billion-molecule docking found new PAMs with a hit rate that was 2.7-fold higher than the million-molecule library and with hits up to 37-fold more potent. Structure-based optimization of ligands from both campaigns led to nanomolar leads, one of which was advanced to animal testing. This PAM displays 100-fold the potency of the standard of care, cinacalcet, in ex vivo organ assays, and reduces serum PTH levels in mice by up to 80% without the hypocalcemia typical of CaSR drugs. Cryo-EM structures with the new PAMs show that they induce residue rearrangements in the binding pockets and promote CaSR dimer conformations that are closer to the G-protein coupled state compared to established drugs. These findings highlight the promise of large library docking for therapeutic leads, especially when combined with experimental structure determination and mechanism. One sentence summaryStructure-based virtual screening uncovers novel CaSR allosteric modulators with enhanced efficacy and less side effects.

biophysics↗