ABSTRACT
In Parkinson's disease (PD), α-synuclein (αS) pathologically impacts the brain, a highly lipid-rich organ. We investigated how alterations in αS or lipid/fatty acid homeostasis affect each other. Lipidomic profiling of human αS-expressing yeast revealed increases in oleic acid (OA, 18:1), diglycerides, and triglycerides. These findings were recapitulated in rodent and human neuronal models of αS dyshomeostasis (overexpression; patient-derived triplication or E46K mutation; E46K mice). Preventing lipid droplet formation or augmenting OA increased αS yeast toxicity; suppressing the OA-generating enzyme stearoyl-CoA-desaturase (SCD) was protective. Genetic or pharmacological SCD inhibition ameliorated toxicity in αS-overexpressing rat neurons. In a C. elegans model, SCD knockout prevented αS-induced dopaminergic degeneration. Conversely, we observed detrimental effects of OA on αS homeostasis: in human neural cells, excess OA caused αS inclusion formation, which was reversed by SCD inhibition. Thus, monounsaturated fatty acid metabolism is pivotal for αS-induced neurotoxicity, and inhibiting SCD represents a novel PD therapeutic approach.
Subject(s)
Antiparkinson Agents/pharmacology , Drug Discovery/methods , Enzyme Inhibitors/pharmacology , Lipid Metabolism/drug effects , Metabolomics/methods , Neurons/drug effects , Parkinson Disease/drug therapy , Stearoyl-CoA Desaturase/antagonists & inhibitors , alpha-Synuclein/toxicity , Animals , Caenorhabditis elegans/drug effects , Caenorhabditis elegans/enzymology , Caenorhabditis elegans/genetics , Cell Line , Cerebral Cortex/drug effects , Cerebral Cortex/enzymology , Cerebral Cortex/pathology , Diglycerides/metabolism , Disease Models, Animal , Dopaminergic Neurons/drug effects , Dopaminergic Neurons/enzymology , Dopaminergic Neurons/pathology , Humans , Induced Pluripotent Stem Cells/drug effects , Induced Pluripotent Stem Cells/enzymology , Induced Pluripotent Stem Cells/pathology , Lipid Droplets/drug effects , Lipid Droplets/enzymology , Mice, Inbred C57BL , Mice, Transgenic , Molecular Targeted Therapy , Nerve Degeneration , Neural Stem Cells/drug effects , Neural Stem Cells/enzymology , Neural Stem Cells/pathology , Neurons/enzymology , Neurons/pathology , Oleic Acid/metabolism , Parkinson Disease/enzymology , Parkinson Disease/genetics , Parkinson Disease/pathology , Rats, Sprague-Dawley , Saccharomyces cerevisiae/drug effects , Saccharomyces cerevisiae/enzymology , Saccharomyces cerevisiae/genetics , Stearoyl-CoA Desaturase/metabolism , Triglycerides/metabolism , alpha-Synuclein/geneticsABSTRACT
Serotonin, a central neuromodulator with ancient ties to feeding and metabolism, is a major driver of body fat loss. However, mechanisms by which central serotonin action leads to fat loss remain unknown. Here, we report that the FLP-7 neuropeptide and its cognate receptor, NPR-22, function as the ligand-receptor pair that defines the neuroendocrine axis of serotonergic body fat loss in Caenorhabditis elegans. FLP-7 is secreted as a neuroendocrine peptide in proportion to fluctuations in neural serotonin circuit functions, and its release is regulated from secretory neurons via the nutrient sensor AMPK. FLP-7 acts via the NPR-22/Tachykinin2 receptor in the intestine and drives fat loss via the adipocyte triglyceride lipase ATGL-1. Importantly, this ligand-receptor pair does not alter other serotonin-dependent behaviours including food intake. For global modulators such as serotonin, the use of distinct neuroendocrine peptides for each output may be one means to achieve phenotypic selectivity.
Subject(s)
Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans/physiology , Neuropeptides/physiology , Receptors, Neuropeptide/physiology , Serotonin/metabolism , AMP-Activated Protein Kinases/metabolism , Adipose Tissue/physiology , Animals , Behavior, Animal/physiology , Eating/physiology , Indoles/pharmacology , Lipid Metabolism/drug effects , Lipid Metabolism/physiology , Mutation , Neurons/physiology , Neuropeptides/metabolism , Neurosecretory Systems/physiology , Piperidines/pharmacology , Receptors, G-Protein-Coupled , Receptors, Neuropeptide/antagonists & inhibitors , Receptors, Neuropeptide/metabolism , Signal Transduction/drug effects , Signal Transduction/physiologyABSTRACT
Serotonin (5-hydroxytryptamine, 5-HT) is an ancient and conserved neuromodulator of energy balance. Despite its importance, the neural circuits and molecular mechanisms underlying 5-HT-mediated control of body fat remain poorly understood. Here, we decipher the serotonergic neural circuit for body fat loss in C. elegans and show that the effects of 5-HT require signaling from octopamine, the invertebrate analog of adrenaline, to sustain body fat loss. Our results provide a potential molecular explanation for the long-observed potent effects of combined serotonergic and adrenergic weight loss drugs. In metabolic tissues, we find that the conserved regulatory adipocyte triglyceride lipase ATGL-1 drives serotonergic fat loss. We show that the serotonergic chloride channel MOD-1 relays a long-range endocrine signal from C. elegans body cavity neurons to control distal ATGL-1 function, via the nuclear receptor NHR-76. Our findings establish a conserved neuroendocrine axis operated by neural serotonergic and adrenergic-like signaling to regulate body fat.
