ResearchIn-Press PreviewNeuroscience Open Access | 10.1172/jci.insight.168594
1Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, United States of America
2Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America
3Children's Hospital of Philadelphia, Philadelphia, United States of America
4Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America
5The City University of New York, Graduate Center - Advanced Science Research Center, Neuroscience Initiative, New York, United States of America
6Department of Cell Biology, UT Southwestern Medical Center, Dallas, United States of America
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1Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, United States of America
2Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America
3Children's Hospital of Philadelphia, Philadelphia, United States of America
4Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America
5The City University of New York, Graduate Center - Advanced Science Research Center, Neuroscience Initiative, New York, United States of America
6Department of Cell Biology, UT Southwestern Medical Center, Dallas, United States of America
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1Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, United States of America
2Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America
3Children's Hospital of Philadelphia, Philadelphia, United States of America
4Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America
5The City University of New York, Graduate Center - Advanced Science Research Center, Neuroscience Initiative, New York, United States of America
6Department of Cell Biology, UT Southwestern Medical Center, Dallas, United States of America
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1Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, United States of America
2Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America
3Children's Hospital of Philadelphia, Philadelphia, United States of America
4Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America
5The City University of New York, Graduate Center - Advanced Science Research Center, Neuroscience Initiative, New York, United States of America
6Department of Cell Biology, UT Southwestern Medical Center, Dallas, United States of America
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1Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, United States of America
2Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America
3Children's Hospital of Philadelphia, Philadelphia, United States of America
4Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America
5The City University of New York, Graduate Center - Advanced Science Research Center, Neuroscience Initiative, New York, United States of America
6Department of Cell Biology, UT Southwestern Medical Center, Dallas, United States of America
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1Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, United States of America
2Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America
3Children's Hospital of Philadelphia, Philadelphia, United States of America
4Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America
5The City University of New York, Graduate Center - Advanced Science Research Center, Neuroscience Initiative, New York, United States of America
6Department of Cell Biology, UT Southwestern Medical Center, Dallas, United States of America
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1Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, United States of America
2Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America
3Children's Hospital of Philadelphia, Philadelphia, United States of America
4Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America
5The City University of New York, Graduate Center - Advanced Science Research Center, Neuroscience Initiative, New York, United States of America
6Department of Cell Biology, UT Southwestern Medical Center, Dallas, United States of America
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1Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, United States of America
2Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America
3Children's Hospital of Philadelphia, Philadelphia, United States of America
4Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America
5The City University of New York, Graduate Center - Advanced Science Research Center, Neuroscience Initiative, New York, United States of America
6Department of Cell Biology, UT Southwestern Medical Center, Dallas, United States of America
Find articles by Teshome, H. in: JCI | PubMed | Google Scholar
1Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, United States of America
2Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America
3Children's Hospital of Philadelphia, Philadelphia, United States of America
4Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America
5The City University of New York, Graduate Center - Advanced Science Research Center, Neuroscience Initiative, New York, United States of America
6Department of Cell Biology, UT Southwestern Medical Center, Dallas, United States of America
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1Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, United States of America
2Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America
3Children's Hospital of Philadelphia, Philadelphia, United States of America
4Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America
5The City University of New York, Graduate Center - Advanced Science Research Center, Neuroscience Initiative, New York, United States of America
6Department of Cell Biology, UT Southwestern Medical Center, Dallas, United States of America
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1Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, United States of America
2Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America
3Children's Hospital of Philadelphia, Philadelphia, United States of America
4Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America
5The City University of New York, Graduate Center - Advanced Science Research Center, Neuroscience Initiative, New York, United States of America
6Department of Cell Biology, UT Southwestern Medical Center, Dallas, United States of America
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1Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, United States of America
2Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America
3Children's Hospital of Philadelphia, Philadelphia, United States of America
4Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America
5The City University of New York, Graduate Center - Advanced Science Research Center, Neuroscience Initiative, New York, United States of America
6Department of Cell Biology, UT Southwestern Medical Center, Dallas, United States of America
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1Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, United States of America
2Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America
3Children's Hospital of Philadelphia, Philadelphia, United States of America
4Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America
5The City University of New York, Graduate Center - Advanced Science Research Center, Neuroscience Initiative, New York, United States of America
6Department of Cell Biology, UT Southwestern Medical Center, Dallas, United States of America
Find articles by He, Y. in: JCI | PubMed | Google Scholar
1Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, United States of America
2Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America
3Children's Hospital of Philadelphia, Philadelphia, United States of America
4Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America
5The City University of New York, Graduate Center - Advanced Science Research Center, Neuroscience Initiative, New York, United States of America
6Department of Cell Biology, UT Southwestern Medical Center, Dallas, United States of America
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1Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, United States of America
2Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America
3Children's Hospital of Philadelphia, Philadelphia, United States of America
4Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America
5The City University of New York, Graduate Center - Advanced Science Research Center, Neuroscience Initiative, New York, United States of America
6Department of Cell Biology, UT Southwestern Medical Center, Dallas, United States of America
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Published April 16, 2024 - More info
Dysregulated lipid homeostasis is emerging as a potential cause of neurodegenerative disorders. However, evidence of errors in lipid homeostasis as a pathogenic mechanism of neurodegeneration remains limited. Here, we show that cerebellar neurodegeneration caused by Sorting Nexin 14 (SNX14) deficiency is associated with lipid homeostasis defects. Recent studies indicate that SNX14 is an inter-organelle lipid transfer protein that regulates lipid transport, lipid droplet (LD) biogenesis, and fatty acid desaturation, suggesting that human SNX14 deficiency belongs to an expanding class of cerebellar neurodegenerative disorders caused by altered cellular lipid homeostasis. To test this hypothesis, we generated a mouse model that recapitulates human SNX14 deficiency at a genetic and phenotypic level. We demonstrate that cerebellar Purkinje cells (PCs) are selectively vulnerable to SNX14 deficiency while forebrain regions preserve their neuronal content. Ultrastructure and lipidomic studies reveal widespread lipid storage and metabolism defects in SNX14 deficient mice. However, pre-degenerating SNX14 deficient cerebella show a unique accumulation of acylcarnitines and depletion of triglycerides. Furthermore, defects in LD content and telolysosome enlargement in pre-degenerating PCs, suggest lipotoxicity as a pathogenic mechanism of SNX14 deficiency. Our work shows a selective cerebellar vulnerability to altered lipid homeostasis and provides a mouse model for future therapeutic studies.