Biology subjects

Htun, S.

Publications and source records attributed to Htun, S..

4 recordsLinked to original sources

bioRxiv2026

Adrenomedullin Restores Mitochondrial Bioenergetics and Rescues Interneuron Phenotypes in Human Models of 22q11.2 Deletion Syndrome

22q11.2 deletion syndrome (22q11.2DS), also known as DiGeorge syndrome, is the strongest genetic risk factor for schizophrenia, yet the cellular mechanisms underlying this vulnerability remain incompletely understood. Using iPSC-derived human subpallial organoids (hSOs) and forebrain assembloids (hFAs), we identified key 22q11.2DS cellular and molecular phenotypes in migrating cortical interneurons and rescued them with Adrenomedullin (ADM), a 52-amino-acid peptide hormone that acts through the CLR/RAMP2 receptor complex. Specifically, we discover that 22q11.2DS interneurons exhibit impaired migration patterns, and that this is associated with excessive mitochondrial fragmentation, reduced oxidative phosphorylation, and dysregulated calcium signaling. Transcriptomic analysis reveals a glycolytic shift and widespread downregulation of oxidative phosphorylation genes. Next, we identify ADM as a potent rescue agent that restores mitochondrial morphology, membrane potential, respiration, calcium homeostasis, actin retrograde flow, and interneuron migration. Mechanistically, we find that ADM signals through two parallel pathways: PKA-mediated DRP1 Ser637 phosphorylation, which promotes mitochondrial fusion, and PLC-mediated calcium signaling, which normalizes actin dynamics. These phenotypes and their rescue are recapitulated in primary developing human cortical tissue carrying the 22q11.2 deletion. Overall, our study establishes a mitochondrial-cytoskeletal axis as a novel biological mechanism underlying the alterations observed in neuronal development in human preclinical models of 22q11.2DS and identifies possible therapeutic molecular targets for 22q11.2DS-associated neuropsychiatric pathology. HIGHLIGHTSO_LIInhibitory neurons in 22q11.2DS organoids and assembloids show mitochondrial fragmentation and impaired migration C_LIO_LIADM rescues mitochondrial morphology, respiration, and interneuron migration C_LIO_LIPKA and PLC pathways mediate separate arms of ADMs rescue mechanism C_LIO_LIPhenotypes and ADM rescue are validated in human cortical tissue C_LI

neuroscience↗

bioRxiv2024

Hypoxia disrupts circadian rhythms in astrocytes and causes synapse engulfment defects

Astrocytes are emerging as key regulators of neuronal synaptic network maturation and function, through control of synaptic pruning. This is important, because individuals with ASD have excess glutamatergic synapses in the cortex, but the biological mechanisms underlying this phenotype remain unclear. Here, we used human cortical organoids (hCO) derived from induced pluripotent stem cells (hiPSCs), to examine the effect of hypoxia on synapse engulfment in human astrocytes at postnatal-equivalent stages of development. We identified that hypoxia significantly inhibits the synaptosome phagocytosis, and that this phenotype is mediated through disruptions in the astrocytic circadian rhythm molecular pathway and subsequent decreased expression of MEGF10. Lastly, we demonstrated that circadian clock disruptions are sufficient to induce these observed phenotypes even in the absence of hypoxia, both in hCOs and within the mouse hippocampus in vivo. Our study uncovers a novel mechanistic link between hypoxia, circadian rhythms disruptions, and synapse pruning by astrocytes, and provides insight into the pathophysiology of ASD, and other neuropsychiatric diseases. Separately, the demonstration of the presence of circadian rhythms in hCOs opens an unprecedented opportunity to dissect the role of circadian clocks in normal brain development and how it contributes to specific diseases of environmental or genetic origin.

neuroscience↗

bioRxiv2023

Adrenomedullin promotes interneuron migration in a dual human model for hypoxic interneuronopathy of prematurity.

Extremely preterm birth (at < 28 postconceptional weeks) leads to brain injury and represents the leading cause of childhood-onset neuropsychiatric diseases. No effective therapeutics exist to reduce the incidence and severity of brain injury of prematurity. Hypoxic events are the most important environmental factor, along with inflammation. Among other developmental processes, the second half of in utero fetal development coincides with the migration of cortical interneurons from the ganglionic eminences into the cortex; this process is thus prone to disruptions following extremely preterm birth. To date, no studies have directly investigated the migration of human cortical inhibitory neurons under hypoxic conditions. Using multi-day confocal live imaging in human forebrain assembloids (hFA) derived from human induced pluripotent stem cells (hiPSCs) and ex vivo developing human brain tissue, we found a substantial reduction in the migration of hypoxic interneurons. Using transcriptomics, we identified adrenomedullin (ADM) as the gene with the highest fold change increase in expression. Based on previous literature about the protective role of supplemental ADM for other injuries, here, we demonstrated that addition of exogenous ADM to the hypoxic media restores the migration defects of interneurons. Lastly, we showed that one of the mechanisms of protection by ADM is through the activation of the cAMP/PKA pathway and subsequent pCREB-dependent rescued expression of a subset of GABA receptors, which are known to promote migration. Overall, in this manuscript we provide the first direct evidence for hypoxia-induced deficits in the migration of human cortical interneurons and identify ADM as a possible target for therapeutic development. SummaryWe identified human cortical interneurons migration deficits under hypoxic conditions and rescued this phenotype using adrenomedullin.

neuroscience↗

bioRxiv2020

Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness

The RNA exosome is an essential ribonuclease complex involved in the processing and degradation of both coding and noncoding RNAs. We present three patients with biallelic variants in EXOSC5, which encodes a structural subunit of the RNA exosome. The common clinical features of these patients comprise failure to thrive, short stature, feeding difficulties, developmental delays that affect motor skills, hypotonia and esotropia. Brain MRI revealed cerebellar hypoplasia and ventriculomegaly. The first patient had a deletion involving exons 5-6 of EXOSC5 and a missense variant, p.Thr114Ile, that were inherited in trans, the second patient was homozygous for p.Leu206His, and the third patient had paternal isodisomy for chromosome 19 and was homozygous for p.Met148Thr. We employed three complementary approaches to explore the requirement for EXOSC5 in brain development and assess the functional consequences of pathogenic variants in EXOSC5. Loss of function for the zebrafish ortholog results in shortened and curved tails and bodies, reduced eye and head size and edema. We modeled pathogenic EXOSC5 variants in both budding yeast and mammalian cells. Some of these variants show defects in RNA exosome function as well as altered interactions with other RNA exosome subunits. Overall, these findings expand the number of genes encoding RNA exosome components that have been implicated in human disease, while also suggesting that disease mechanism varies depending on the specific pathogenic variant.

genetics↗