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Accumulation of alkyl-lysophosphatidylcholines in Niemann-Pick disease type C1.
Mishra, Sonali; Kell, Pamela; Scherrer, David; Dietzen, Dennis J; Vite, Charles H; Berry-Kravis, Elizabeth; Davidson, Cristin; Cologna, Stephanie M; Porter, Forbes D; Ory, Daniel S; Jiang, Xuntian.
Afiliação
  • Mishra S; Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
  • Kell P; Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
  • Scherrer D; Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
  • Dietzen DJ; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.
  • Vite CH; Department of Clinical Studies and Advanced Medicine, University of Pennsylvania School of Veterinary Medicine, PA, USA.
  • Berry-Kravis E; Department of Pediatrics, Neurological Sciences and Anatomy and Cell Biology, Rush University Medical Center, Chicago, IL, USA.
  • Davidson C; Section on Molecular Dysmorphology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS, Bethesda, MD, USA.
  • Cologna SM; Department of Chemistry, University of Illinois Chicago, Chicago, IL, USA.
  • Porter FD; Section on Molecular Dysmorphology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS, Bethesda, MD, USA.
  • Ory DS; Arbor Biotechnologies, Cambridge, MA, USA.
  • Jiang X; Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: jiangxuntian@wustl.edu.
J Lipid Res ; 65(8): 100600, 2024 Aug.
Article em En | MEDLINE | ID: mdl-39048052
ABSTRACT
Lysosomal function is impaired in Niemann-Pick disease type C1 (NPC1), a rare and inherited neurodegenerative disorder, resulting in late endosomal/lysosomal accumulation of unesterified cholesterol. The precise pathogenic mechanism of NPC1 remains incompletely understood. In this study, we employed metabolomics to uncover secondary accumulated substances in NPC1. Our findings unveiled a substantial elevation in the levels of three alkyl-lysophosphatidylcholine [alkyl-LPC, also known as lyso-platelet activating factor (PAF)] species in NPC1 compared to controls across various tissues, including brain tissue from individuals with NPC1, liver, spleen, cerebrum, cerebellum, and brain stem from NPC1 mice, as well as in both brain and liver tissue from NPC1 cats. The three elevated alkyl-LPC species were as follows LPC O-160, LPC O-181, and LPC O-180. However, the levels of PAF 160, PAF 181, and PAF 180 were not altered in NPC1. In the NPC1 feline model, the brain and liver alkyl-LPC levels were reduced following 2-hydroxypropyl-ß-cyclodextrin (HPßCD) treatment, suggesting that alkyl-LPCs are secondary storage metabolites in NPC1 disease. Unexpectedly, cerebrospinal fluid (CSF) levels of LPC O-160 and LPC O-181 were decreased in individuals with NPC1 compared to age-appropriate comparison samples, and their levels were increased in 80% of participants 2 years after intrathecal HPßCD treatment. The fold increases in CSF LPC O-160 and LPC O-181 levels were more pronounced in responders compared to nonresponders. This study identified alkyl-LPC species as secondary storage metabolites in NPC1 and indicates that LPC O-160 and LPC O-181, in particular, could serve as potential biomarkers for tracking treatment response in NPC1 patients.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Lisofosfatidilcolinas / Doença de Niemann-Pick Tipo C Limite: Adolescent / Adult / Animals / Child / Child, preschool / Female / Humans / Male Idioma: En Revista: J Lipid Res Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Estados Unidos
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Lisofosfatidilcolinas / Doença de Niemann-Pick Tipo C Limite: Adolescent / Adult / Animals / Child / Child, preschool / Female / Humans / Male Idioma: En Revista: J Lipid Res Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Estados Unidos