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Tahanis, A.

Publications and source records attributed to Tahanis, A..

2 recordsLinked to original sources
bioRxiv2025

Glucocerebrosidase Deficiency Dysregulates Human Astrocyte Lipid Metabolism

BackgroundDeficiency in the lysosomal enzyme, glucocerebrosidase (GCase), caused by mutations in the GBA1 gene, is the most common genetic risk factor for Parkinsons disease (PD). However, the consequence of reduced enzyme activity within neural cell sub-types remains ambiguous. Thus, the purpose of this study was to define the effect of GCase deficiency specifically in human astrocytes and test their non-cell autonomous influence upon dopaminergic neurons in a midbrain organoid model of PD. MethodsWild-type (GBA+/+), N370S mutant (GBA+/N370), and GBA1 knockout (GBA-/-) astrocytes were rapidly and directly induced from human pluripotent stem cells (hPSCs) via transcription factor-based differentiation. These astrocytes were extensively characterized for GCase-dependent phenotypes using immunocytochemistry, organoid coculture, enzymatic assays, lipid tracers, transcriptomics, and lipidomics. ResultshPSC lines were rapidly induced into astrocytes and enzymatic assays confirmed that GBA-/- astrocytes completely lacked GCase activity, while GBA+/N370 preserved partial activity. GBA-/-, but not GBA+/N370S, exhibited lysosomal alterations, with enlarged lysosomes and glucosylceramide (GlcCer) accumulation. GCase deficiency also exacerbated TNF-alpha-induced secretion of the inflammatory biomarker, CCL2. In midbrain organoids, GCase activity did not modulate the ability of astrocytes to support dopamine neuron production and survival. Lipidomics revealed a GBA-/--specific increase in sphingomyelin, and a decrease of triglycerides. Direct rescue of GCase activity with GBA1 mRNA treatment reduced GlcCer accumulation. Astrocytes exhibited a relatively high uptake and storage of fatty acid analogs as lipid droplets, in comparison to neurons, and this process was impaired in GBA-/- astrocytes. Lastly, GBA-/- astrocytes accumulate neuronal membrane-derived GlcCer. These findings highlight the critical role of astrocytic GCase in lipid metabolism and its neuronal influence. ConclusionGCase deficiency does not inhibit human astrocyte differentiation nor cause a non-cell autonomous neurotoxic effect upon dopaminergic neurons within midbrain organoids. However, it does elicit enhanced inflammatory reactivity, accumulation of GlcCer, and a distinct lipidomic profile, indicating impaired lipid metabolism in astrocytes that can dysregulate neuron-astrocyte intercellular signaling. Overall, these insights underscore dysfunctional astrocyte lipid metabolism as a high priority therapeutic target in Parkinsons disease and related neurodegenerative disorders. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=170 SRC="FIGDIR/small/632210v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@1b1138forg.highwire.dtl.DTLVardef@7b26aborg.highwire.dtl.DTLVardef@127b950org.highwire.dtl.DTLVardef@f74a59_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗
bioRxiv2024

Non-canonical adrenergic neuromodulation of motoneuron intrinsic excitability through beta-receptors in wild-type and ALS mice

Homeostatic feedback loops are essential to stabilize the activity of neurons and neuronal networks. It has been hypothesized that, in the context of Amyotrophic Lateral Sclerosis (ALS), an excessive gain in feedback loops might hyper- or hypo-excite motoneurons (MNs) and contribute to the pathogenesis. Here, we investigated how the neuromodulation of MN intrinsic properties is homeostatically controlled in presymptomatic adult SOD1(G93A) mice and in the age-matched control WT mice. First, we determined that {beta}2 and {beta}3-adrenergic receptors, which are Gs-coupled receptors and subject to tight and robust feedback loops, are specifically expressed in spinal MNs of both SOD1 and WT mice at P45. We then demonstrated that these receptors elicit a so-far overlooked neuromodulation of the firing and excitability properties of MNs. These electrical properties are homeostatically regulated following receptor engagement, which triggers ion channel transcriptional changes and downregulates those receptors. These homeostatic feedbacks are not dysregulated in presymptomatic SOD1 mice, and they set the MN excitability upon {beta}-adrenergic neuromodulation.

neuroscience↗