Inhibition of sphingolipid synthesis improves outcomes and survival in GARP mutant

Animals Disease Models, Animal Endosomes / metabolism Fatty Acids, Monounsaturated / pharmacology Female Fibroblasts / metabolism Golgi Apparatus / metabolism Male Membrane Proteins / genetics Mice Mice, Neurologic Mutants Motor Neuron Disease / genetics Motor Neurons / metabolism Mouse Embryonic Stem Cells Mutation Nervous System Malformations / metabolism Neurodegenerative Diseases / metabolism Protein Transport Proteomics Sphingolipids / metabolism Vesicular Transport Proteins / metabolism
amyotrophic lateral sclerosis myriocin neurodegeneration sphingolipid wobbler mice

Journal

Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876

Informations de publication

Date de publication:
12 05 2020
Historique:
pubmed: 30 4 2020
medline: 22 8 2020
entrez: 30 4 2020
Statut: ppublish

Résumé

Numerous mutations that impair retrograde membrane trafficking between endosomes and the Golgi apparatus lead to neurodegenerative diseases. For example, mutations in the endosomal retromer complex are implicated in Alzheimer's and Parkinson's diseases, and mutations of the Golgi-associated retrograde protein (GARP) complex cause progressive cerebello-cerebral atrophy type 2 (PCCA2). However, how these mutations cause neurodegeneration is unknown. GARP mutations in yeast, including one causing PCCA2, result in sphingolipid abnormalities and impaired cell growth that are corrected by treatment with myriocin, a sphingolipid synthesis inhibitor, suggesting that alterations in sphingolipid metabolism contribute to cell dysfunction and death. Here we tested this hypothesis in

Identifiants

DOI: 10.1073/pnas.1913956117 PMID: 32345721 PMC: PMC7229683
pubmed: 32345721
pii: 1913956117
doi: 10.1073/pnas.1913956117
pmc: PMC7229683
doi:

Substances chimiques

Fatty Acids, Monounsaturated 0
Lrrc32 protein, mouse 0
Membrane Proteins 0
Sphingolipids 0
Vesicular Transport Proteins 0
thermozymocidin YRM4E8R9ST

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

10565-10574

Subventions

Organisme : NINDS NIH HHS
ID : R37 NS083524
Pays : United States
Organisme : CIHR
Pays : Canada
Organisme : NINDS NIH HHS
ID : R01 NS110395
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA006516
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : BLRD VA
ID : I01 BX002978
Pays : United States

Déclaration de conflit d'intérêts

The authors declare no competing interest.

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Auteurs

Constance S Petit (CS)

Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Harvard University, Boston, MA 02115.
Department of Cell Biology, Harvard Medical School, Boston, MA 02115.

Jane J Lee (JJ)

Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Harvard University, Boston, MA 02115.
Department of Cell Biology, Harvard Medical School, Boston, MA 02115.

Sebastian Boland (S)

Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Harvard University, Boston, MA 02115.
Department of Cell Biology, Harvard Medical School, Boston, MA 02115.

Sharan Swarup (S)

Department of Cell Biology, Harvard Medical School, Boston, MA 02115.

Romain Christiano (R)

Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Harvard University, Boston, MA 02115.
Department of Cell Biology, Harvard Medical School, Boston, MA 02115.

Zon Weng Lai (ZW)

Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Harvard University, Boston, MA 02115.
Department of Cell Biology, Harvard Medical School, Boston, MA 02115.

Niklas Mejhert (N)

Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Harvard University, Boston, MA 02115.
Department of Cell Biology, Harvard Medical School, Boston, MA 02115.

Shane D Elliott (SD)

Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Harvard University, Boston, MA 02115.
Department of Cell Biology, Harvard Medical School, Boston, MA 02115.

David McFall (D)

Department of Pathology, University of California, San Francisco, CA 94143.

Sara Haque (S)

Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Harvard University, Boston, MA 02115.
Department of Cell Biology, Harvard Medical School, Boston, MA 02115.

Eric J Huang (EJ)

Department of Pathology, University of California, San Francisco, CA 94143.
ORCID: 0000-0002-5381-3801

Roderick T Bronson (RT)

Department of Immunology, Harvard Medical School, Boston, MA 02115.

J Wade Harper (JW)

Department of Cell Biology, Harvard Medical School, Boston, MA 02115.

Robert V Farese (RV)

Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Harvard University, Boston, MA 02115; Robert@hsph.harvard.edu twalther@hsph.harvard.edu.
Department of Cell Biology, Harvard Medical School, Boston, MA 02115.
Broad Institute of MIT and Harvard University, Cambridge, MA 02124.

Tobias C Walther (TC)

Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Harvard University, Boston, MA 02115; Robert@hsph.harvard.edu twalther@hsph.harvard.edu.
Department of Cell Biology, Harvard Medical School, Boston, MA 02115.
Broad Institute of MIT and Harvard University, Cambridge, MA 02124.
Howard Hughes Medical Institute, Harvard University, Boston, MA 02115.

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Classifications MeSH

Recherchemedicale.com › Eucaryotes › Animaux › Inhibition of sphingolipid synthesis improves...
Recherchemedicale.com › Techniques d'investigation › Modèles théoriques › Modèles biologiques › Modèles animaux de maladie humaine › Inhibition of sphingolipid synthesis improves...
Recherchemedicale.com › Cellules › Structures cellulaires › Espace intracellulaire › Cytoplasme › Structures cytoplasmiques › Organites › Vésicules cytoplasmiques › Vésicules de transport › Endosomes › Inhibition of sphingolipid synthesis improves...
Recherchemedicale.com › Lipides › Acides gras › Acides gras insaturés › Acides gras monoinsaturés › Inhibition of sphingolipid synthesis improves...
Recherchemedicale.com › Cellules › Cellules du tissu conjonctif › Fibroblastes › Inhibition of sphingolipid synthesis improves...
Recherchemedicale.com › Cellules › Structures cellulaires › Espace intracellulaire › Cytoplasme › Structures cytoplasmiques › Organites › Appareil de Golgi › Inhibition of sphingolipid synthesis improves...
Recherchemedicale.com › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Inhibition of sphingolipid synthesis improves...
Recherchemedicale.com › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Inhibition of sphingolipid synthesis improves...
Recherchemedicale.com › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souches mutantes de souris › Mutants neurologiques de souris › Inhibition of sphingolipid synthesis improves...
Recherchemedicale.com › Maladies du système nerveux › Maladies neuromusculaires › Maladies du motoneurone › Inhibition of sphingolipid synthesis improves...
Recherchemedicale.com › Cellules › Neurones › Neurones efférents › Motoneurones › Inhibition of sphingolipid synthesis improves...
Recherchemedicale.com › Cellules › Cellules souches › Cellules souches pluripotentes › Cellules souches embryonnaires › Cellules souches embryonnaires de souris › Inhibition of sphingolipid synthesis improves...
Recherchemedicale.com › Phénomènes génétiques › Variation génétique › Mutation › Inhibition of sphingolipid synthesis improves...
Recherchemedicale.com › Malformations et maladies congénitales, héréditaires et néonatales › Malformations › Malformations du système nerveux › Inhibition of sphingolipid synthesis improves...
Recherchemedicale.com › Maladies du système nerveux › Maladies neurodégénératives › Inhibition of sphingolipid synthesis improves...
Recherchemedicale.com › Métabolisme › Transport biologique › Transport des protéines › Inhibition of sphingolipid synthesis improves...
Recherchemedicale.com › Disciplines des sciences naturelles › Chimie › Biochimie › Protéomique › Inhibition of sphingolipid synthesis improves...
Recherchemedicale.com › Lipides › Lipides membranaires › Sphingolipides › Inhibition of sphingolipid synthesis improves...
Recherchemedicale.com › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines du transport vésiculaire › Inhibition of sphingolipid synthesis improves...