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Reduction of glutamate neurotoxicity: A novel therapeutic approach for Niemann-Pick disease, type C1.
Cougnoux, Antony; Yerger, Julia C; Fellmeth, Mason; Serra-Vinardell, Jenny; Navid, Fatemeh; Wassif, Christopher A; Cawley, Niamh X; Porter, Forbes D.
Afiliación
  • Cougnoux A; Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
  • Yerger JC; Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
  • Fellmeth M; Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
  • Serra-Vinardell J; Human Biochemical Genetics Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
  • Navid F; Pediatric Translational Research Branch, National Institute of Arthritis and Musculoskeletal and Skin Disease, National Institutes of Health, Bethesda, MD, USA.
  • Wassif CA; Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
  • Cawley NX; Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
  • Porter FD; Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA. Electronic address: fdporter@mail.nih.gov.
Mol Genet Metab ; 134(4): 330-336, 2021 12.
Article en En | MEDLINE | ID: mdl-34802899
Niemann-Pick disease, type C1 is a progressive, lethal, neurodegenerative disorder due to endolysosomal storage of unesterified cholesterol. Cerebellar ataxia, as a result of progressive loss of cerebellar Purkinje neurons, is a major symptom of Nieman-Pick disease, type C1. Comparing single cell RNAseq data from control (Npc1+/+) and mutant (Npc1-/-) mice, we observed significantly decreased expression of Slc1a3 in Npc1-/- astrocytes. Slc1a3 encodes a glutamate transporter (GLAST, EAAT1) which functions to decrease glutamate concentrations in the post synaptic space after neuronal firing. Glutamate is an excitatory neurotransmitter and elevated extracellular levels of glutamate can be neurotoxic. Impaired EAAT1 function underlies type-6 episodic ataxia, a rare disorder with progressive cerebellar dysfunction, thus suggesting that impaired glutamate uptake in Niemann-Pick disease, type C1 could contribute to disease progression. We now show that decreased expression of Slc1a3 in Npc1-/- mice has functional consequences that include decreased surface protein expression and decreased glutamate uptake by Npc1-/- astrocytes. To test whether glutamate neurotoxicity plays a role in Niemann-Pick disease, type C1 progression, we treated NPC1 deficient mice with ceftriaxone and riluzole. Ceftriaxone is a ß-lactam antibiotic that is known to upregulate the expression of Slc1a2, an alternative glial glutamate transporter. Although ceftriaxone increased Slc1a2 expression, we did not observe a treatment effect in NPC1 mutant mice. Riluzole is a glutamate receptor antagonist that inhibits postsynaptic glutamate receptor signaling and reduces the release of glutamate. We found that treatment with riluzole increased median survival in Npc1-/- by 12%. Given that riluzole is an approved drug for the treatment of amyotrophic lateral sclerosis, repurposing of this drug may provide a novel therapeutic approach to decrease disease progression in Niemann-Pick disease type, C1 patients.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Contexto en salud: 1_ASSA2030 Problema de salud: 1_doencas_nao_transmissiveis Asunto principal: Ceftriaxona / Ácido Glutámico / Riluzol / Enfermedad de Niemann-Pick Tipo C Límite: Animals / Female / Humans / Male Idioma: En Revista: Mol Genet Metab Asunto de la revista: BIOLOGIA MOLECULAR / BIOQUIMICA / METABOLISMO Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Contexto en salud: 1_ASSA2030 Problema de salud: 1_doencas_nao_transmissiveis Asunto principal: Ceftriaxona / Ácido Glutámico / Riluzol / Enfermedad de Niemann-Pick Tipo C Límite: Animals / Female / Humans / Male Idioma: En Revista: Mol Genet Metab Asunto de la revista: BIOLOGIA MOLECULAR / BIOQUIMICA / METABOLISMO Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos
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