Biology subjects

Friedecky, D.

Publications and source records attributed to Friedecky, D..

3 recordsLinked to original sources

bioRxiv2026

GPR180 deficiency impairs mitochondrial function and insulin secretion in pancreatic β-cells

ObjectiveG protein-coupled receptor 180 (GPR180) has been implicated in systemic energy metabolism, primarily in adipose tissue and the liver. Given impaired whole-body glucose tolerance following GPR180 dysfunction, we aimed to determine whether GPR180 regulates pancreatic {beta}-cell function. We investigated whether GPR180 contributes to {beta}-cell insulin secretion by modulating metabolic processes that couple glucose sensing to mitochondrial energy production. MethodsPhenotyping of whole-body (Gpr180 -/-) and {beta} cell-specific Gpr180 (bGpr180-KO) knockout mice was combined with gain- and loss-of-function studies in MIN6 cells. Glucose-stimulated insulin secretion, pancreatic endocrine architecture and identity, transcriptomic and metabolic profiles, as well as mitochondrial function were assessed using in vivo and in vitro approaches, including metabolic challenge tests, histology, RNA sequencing, targeted metabolomics, respirometry, and transmission electron microscopy. ResultsLoss of GPR180 impaired first-phase insulin secretion and glucose tolerance without affecting insulin sensitivity. These defects were {beta}-cell-autonomous, as confirmed in the bGpr180-KO mice and in MIN6 cells. Functional studies revealed that GPR180 regulates mitochondrial substrate utilization, anaplerotic support of the TCA cycle, and ATP generation without affecting glucose uptake or mitochondrial biogenesis. In particular, Gpr180-deficient {beta} cells showed mitochondrial membrane depolarization, reduced oxygen consumption, and endoplasmic reticulum remodeling, altering the local mitochondrial microenvironment. In vivo, Gpr180 deletion in {beta} cells led to downregulation of mitochondrial gene programs in islets, along with altered endocrine cell identity. ConclusionsGPR180 is a previously unrecognized regulator of pancreatic {beta}-cell metabolic competence and identity, linking defects in insulin secretion with alterations in mitochondrial function and endocrine cell identity. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=198 SRC="FIGDIR/small/720098v1_ufig1.gif" ALT="Figure 1"> View larger version (87K): org.highwire.dtl.DTLVardef@1f24a65org.highwire.dtl.DTLVardef@1f2371eorg.highwire.dtl.DTLVardef@10096a5org.highwire.dtl.DTLVardef@1a242be_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2025

ABCA7 deficiency exacerbates glutamate excitotoxicity in Alzheimer's disease mice -- a new pharmacological target for Glu-related neurotoxicity

Increasing attention has been directed towards the perturbation of glutamate (Glu) and {gamma}-aminobutyric acid (GABA) homeostasis during the pathogenesis of Alzheimers disease (AD). The prevailing disequilibrium, stemming from hyperactivation of the glutamatergic system, culminates in progressive neuronal impairment and cognitive deterioration. This study aimed to elucidate the contributory role of the ATP-binding cassette transporter A7 (ABCA7), identified as the second most critical genetic determinant in AD, in glutamatergic-associated neurotoxicity. This endeavor sought to advance molecular comprehension of neurological disorders where Glu-GABA neurotransmission represents a pivotal pharmacotherapeutic target. Utilizing multi-omics approaches, we rigorously analyzed four distinct mouse models, both with and without APPtg and ABCA7 expression, to simulate varied pathological and ABCA7-deficient states. Our results revealed amyloid-beta (A{beta}) deposition as a catalyst for surging glutamatergic transmission. Notably, ABCA7 ablation exacerbated glutamatergic-induced neurotoxicity, attributed to diminished enzymatic activity related to neurotransmitter degradation and amplified expression levels of specific neurotransmitter transport proteins and receptor subunits, notably NMDA, AMPA, and GABAA. These findings furnish the first comprehensive description elucidating ABCA7s amplification of neurotoxic effects through modulation of Glu-GABA neurotransmission systems in neurodegenerative contexts, primarily mediated by lipid interaction. The evidence underscores ABCA7s imperative role in shaping future pharmacological strategies aimed at counteracting neurodegeneration precipitated by Glu-mediated neurotoxicity. This research advances the frontier for therapeutic exploration to ameliorate the deleterious neural consequences characteristic of neurodegenerative pathologies. HighlightsO_LIAlterations within the ABCA7 transporter locus constitute the second most significant genetic predisposition factor for Alzheimers disease (AD), subsequent to the influence of the APOE4 allele. C_LIO_LIExcessive stimulation of glutamatergic neurotransmission culminates in excitotoxicity, leading to the gradual demise of neuronal populations due to pathological hyperactivity. C_LIO_LIIn murine models with wild-type genetics, the absence of ABCA7 results in diminished functionality of both the glutamatergic and GABAergic neurotransmitter systems. C_LIO_LIConversely, in mouse models engineered to mimic Alzheimers pathology, deficiency in ABCA7 exacerbates glutamate-induced neurotoxicity. C_LIO_LIDuring amyloid-{beta} accumulation, the absence of ABCA7 correlates with an elevation in specific lipid levels, potentially contributing to neurodegenerative processes. C_LIO_LIFrom a therapeutic standpoint, pharmacological activation of ABCA7 may mitigate the neuronal death associated with glutamate overactivation in individuals afflicted by neurodegenerative disorders. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/666774v2_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@1491b86org.highwire.dtl.DTLVardef@ae3bb3org.highwire.dtl.DTLVardef@d1716dorg.highwire.dtl.DTLVardef@6dd7a2_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

Changes in lipid metabolism track with the progression of neurofibrillary pathology in tauopathies.

BackgroundAbnormal aggregation of tau protein that leads to brain inclusions is a common feature of neurodegenerative disorders called tauopathies. Recent evidence suggests the involvement of lipid metabolic deregulations in the pathogenesis of tauopathies. However, the role of tau protein in the regulation of lipid metabolism is much less characterized and not well understood. MethodsWe used a transgenic rat model for tauopathy to reveal metabolic alterations induced by neurofibrillary pathology. Transgenic rats express a tau fragment truncated at the N-and C-terminals. For phenotypic profiling, we performed targeted metabolomic and lipidomic analysis of brain tissue, CSF, and plasma, based on the LC-MS platform. To monitor disease progression, we employed samples from transgenic and control rats aged 4, 6, 8, 10, 12, and 14 months. To study neuron-glia interplay in lipidome changes induced by pathological tau we used well well-established multicomponent cell model system. Univariate and multivariate statistical approaches were used for data evaluation. ResultsWe showed that tau has an important role in the deregulation of lipid metabolism. In the lipidomic study, pathological tau was associated with higher production of lipids participating in protein fibrillization, membrane reorganization, and inflammation. Interestingly, significant changes have been found in the early stages of tauopathy before the formation of high-molecular-weight tau aggregates and neurofibrillary pathology. Increased secretion of pathological tau protein in vivo and in vitro induced upregulated production of phospholipids and sphingolipids and accumulation of lipid droplets in microglia. During the later stages of tauopathy, we found a connection between the transition of tau into an insoluble fraction and changes in brain metabolism. The results showed that dysregulation of lipid composition by pathological tau leads to disruption of the microenvironment and further propagation of pathology. ConclusionOur results revealed that lipid metabolism is significantly affected during different stages of tau pathology and provide new evidence that supports the contribution of pathological tau proteins in individual lipid pathways. Our data suggests that biologically active membrane lipids such as phospholipids and sphingolipids could represent new potential next-generation therapeutic targets in tauopathies.

neuroscience↗