Biology subjects

Lopez-Ramirez, A.

Publications and source records attributed to Lopez-Ramirez, A..

5 recordsLinked to original sources

bioRxiv2025

Variants in glycine decarboxylase activate mechanisms of mitochondrial energy metabolism in the brain.

Brain energy metabolism is produced from glucose by mitochondrial oxidative phosphorylation. Variants in the mitochondrial enzyme glycine decarboxylase (GLDC) cause a rare neurological disease, non-ketotic hyperglycinemia (NKH), with expected hallmarks of brain glycine elevation and responsiveness to folate deficiency that are equivalent to the severity of Gldc mutations. We remarkably find that brains of young- attenuated mutant mice with a 1.5-fold increase in glycine are reduced > 5-fold in GLDC, show a decline in both the mitochondrial lipoyl-transfer protein GCSH and lipoylation of the pyruvate dehydrogenase (PDH) complex, as well as concomitant rise in signatures of astrocyte mitochondrial {beta}-oxidation of fatty acids and activation of neuronal PDH. Our findings suggest a novel GLDC mechanism of remodeling mitochondrial energy systems throughout the brain, established early in and sustained throughout post-natal NKH disease.

neuroscience↗

bioRxiv2025

Chronic HDACi emends microglial differentiation and neurological disease in a mouse model of intellectual disability

Defect in lysine-specific methyltransferase 2D (KMT2D) underlies a rare intellectual disability disorder, Kabuki Syndrome (KS). We show that in addition to reduction in post-natal neurogenesis, KS mice present small, arrested hippocampal microglia which single cell RNA sequence analyses revealed as globally downregulated, occupying neither activated nor surveillance states. Weekly administration of a triple combination formulation (TCF) containing the FDA-approved HDAC inhibitor Vorinostat, HPBCD and PEG-400 for three months, boosted microglia. Transcriptomic, pseudotime cell trajectory analyses, imaging and behavioral data suggest that TCF differentiated KS microglia from arrested to non-diseased and non-activated surveillance forms by selective acetylation of histone H3, that restored the open chromatin mark H3K4me3 independent of Kmt2D, to improve cognitive and nociceptive responses. Wild-type microglia showed no substantial transcriptional or histone changes, intimating normal heterochromatin resisted TCF. These findings reveal a novel chromatin-mediated mechanism of microglial differentiation uncoupled from activation, with therapeutic potential for KS and related disorders.

neuroscience↗

bioRxiv2025

Astrocyte and neurogenic mechanisms of protective gene therapy prevent brain disease and death due to non-ketotic hyperglycinemia

Genetic defects in glycine decarboxylase (GLDC) cause non-ketotic hyperglycinemia (NKH), a rare and frequently fatal neurometabolic disease, which lacks FDA-approved therapies. We characterized CRISPR Cas9-edited humanized mice expressing a prevalent clinical mutation after administration with a single intraperitoneal dose of a novel recombinant of adeno-associated viral vector 9 expressing GLDC (rAAV9-GLDC). Long term biological activity of rAAV9-GLDC was first validated by assessment of its systemic efficacy over five and ten months in mice. Access of rAAV9 to the brain was confirmed by tracking green fluorescent protein (GFP) after a single intraperitoneal dose of rAAV9-GFP. Over five months, control mock treated GFP-mice showed reduction in astrocytes but not microglia, oligodendrocytes or neurons in the brain. 37% of these animals suffered long term neurological disease and/or death. rAAV9-GLDC boosts astrogenesis without triggering an inflammatory response and confers 100% protection against disease progression and fatality due to NKH.

neuroscience↗

bioRxiv2023

Transcriptomic Characterization Reveals Disrupted Medium Spiny Neuron Trajectories in Huntington's Disease and Possible Therapeutic Avenues

Huntingtons disease (HD) is a neurodegenerative disorder caused by an expansion of CAG repeats in exon 1 of the HTT gene, ultimately resulting in the generation of a mutant HTT (mHTT) protein. Although mHTT is expressed in various tissues, it significantly affects medium spiny neurons (MSNs) in the striatum, resulting in their loss and the subsequent motor function impairment in HD. While HD symptoms typically emerge in midlife, disrupted MSN neurodevelopment has an important role. To explore the effects of mHTT on MSN development, we differentiated HD induced pluripotent stem cells (iPSC) and isogenic controls into neuronal stem cells, and then generated a developing MSN population encompassing early, intermediate progenitors, and mature MSNs. Single-cell RNA sequencing revealed that the developmental trajectory of MSNs in our model closely emulated the trajectory of fetal striatal neurons. However, in the HD MSN cultures, the differentiation process downregulated several crucial genes required for proper MSN maturation, including Achaete-scute homolog 1 and members of the DLX family of transcription factors. Our analysis also uncovered a progressive dysregulation of multiple HD-related pathways as the MSNs matured, including the NRF2-mediated oxidative stress response and mitogen-activated protein kinase signaling. Using the transcriptional profile of developing HD MSNs, we searched the L1000 dataset for small molecules that induce the opposite gene expression pattern. Our analysis pinpointed numerous small molecules with known benefits in HD models, as well as previously untested novel molecules. A top novel candidate, Cerulenin, partially restored the DARPP-32 levels and electrical activity in HD MSNs, and also modulated genes involved in multiple HD-related pathways.

neuroscience↗

bioRxiv2022

Proteomic Analysis of Huntington's Disease Medium Spiny Neurons Identifies Alterations in Lipid Droplets

Huntingtons disease (HD) is a neurodegenerative disease caused by a CAG repeat expansion in the Huntingtin (HTT) gene. The resulting polyglutamine (polyQ) tract alters the function of the HTT protein. Although HTT is expressed in different tissues, the medium spiny projection neurons (MSNs) in the striatum are particularly vulnerable in HD. Thus, we sought to define the proteome of human HD patient-derived MSNs. We differentiated HD72 induced pluripotent stem cells and isogenic controls into MSNs and carried out quantitative proteomic analysis by two approaches. First, using data-dependent acquisitions with FAIMS (FAIMS-DDA) for label-free quantification on the Orbitrap Lumos mass spectrometer, we identified 6,323 proteins with at least two unique peptides (FDR [≤] 0.01). Of these, 901 proteins were significantly altered in the HD72-MSNs, compared to isogenic controls. Second, we quantitatively validated protein candidates by comprehensive data-independent acquisitions on a TripleTOF 6600 mass spectrometer quantifying 3,106 proteins with at least two unique peptides. Functional enrichment analysis identified pathways related to the extracellular matrix, including TGF-y regulation of extracellular matrix, epithelial-mesenchymal transition, DNA replication, senescence, cardiovascular system, organism development, regulation of cell migration and locomotion, aminoglycan glycosaminoglycan proteoglycan, growth factor stimulus and fatty acid processes. Conversely, processes associated with the downregulated proteins included neurogenesis-axogenesis, the brain-derived neurotrophic factor-signaling pathway, Ephrin-A: EphA pathway, regulation of synaptic plasticity, triglyceride homeostasis cholesterol, plasmid lipoprotein particle immune response, interferon-{gamma} signaling, immune system major histocompatibility complex, lipid metabolism and cellular response to stimulus. Moreover, proteins involved in the formation and maintenance of axons, dendrites, and synapses (e.g., Septin protein members) are dysregulated in HD72-MSNs. Importantly, lipid metabolism pathways were altered, and we found that lipid droplets accumulated in the HD72-MSNs, suggesting a deficit in lipophagy. Our proteomics analysis of HD72-MSNs identified relevant pathways that are altered in MSNs and confirm current and new therapeutic targets for HD.

neuroscience↗