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Investigation of 2-Hydroxypropyl-ß-Cyclodextrin Treatment in a Neuronal-Like Cell Model of Niemann-Pick Type C Using Quantitative Proteomics.
Cougnoux, Antony; Pergande, Melissa R; Serna-Perez, Fidel; Cologna, Stephanie M.
Afiliação
  • Cougnoux A; Department of Cell and Molecular Biology, Karolinska Institutet and Science for Life Laboratory, Solna 171 65, Sweden.
  • Pergande MR; Department of Chemistry, University of Illinois Chicago, Chicago, Illinois 60607, United States.
  • Serna-Perez F; Department of Chemistry, University of Illinois Chicago, Chicago, Illinois 60607, United States.
  • Cologna SM; Department of Chemistry, University of Illinois Chicago, Chicago, Illinois 60607, United States.
J Am Soc Mass Spectrom ; 34(4): 668-675, 2023 Apr 05.
Article em En | MEDLINE | ID: mdl-36920149
Niemann-Pick, type C (NPC) is a fatal, neurovisceral lysosomal storage disorder with progressive neurodegeneration and no FDA-approved therapy. Significant efforts have been focused on the development of therapeutic options, and 2-hydroxypropyl-ß-cyclodextrin (HP-b-CD) has emerged as a promising candidate. In cell culture, HP-b-CD ameliorates cholesterol storage in endo/lysosomes, a hallmark of the disorder. Furthermore, in animal studies, treatment with HP-b-CD delays neurodegeneration and extends lifespan. While HP-b-CD has been promising in vitro and in vivo, a clear understanding of the mechanism(s) of action is lacking. Utilizing a neuron-like cell culture model of SH-SY5Y differentiated cells and U18666A to induce the NPC phenotype, we report here a large-scale mass-spectrometry-based proteomic study to evaluate proteome changes upon treatment with these small molecules. In this study, we show that differentiated SH-SY5Y cells display morphological changes representative of neuronal-like cells along with increased levels of proliferation markers. Inhibition of the NPC cholesterol transporter 1 protein by U18666A resulted in increased levels of known NPC markers including SCARB2/LIMP2 and LAMP2. Finally, investigation of HP-b-CD treatment was performed where we observe that, although HP-b-CD reduces cholesterol storage, levels of NPC1 and NPC2 are not normalized to control levels. This finding further supports the need for a proteostasis strategy for NPC drug development. Moreover, proteins that were dysregulated in the U18666A model of NPC and normalized to control levels suggest that HP-b-CD promotes exocytosis in this neuron-like model. Utilizing state of the art mass spectrometry analysis, these data demonstrate newly reported changes with pharmacological perturbations related to NPC disease and provide insight into the mechanisms of HP-b-CD as a potential therapeutic.
Assuntos

Texto completo: 1 Coleções: 01-internacional Temas: Geral / Tipos_de_cancer / Outros_tipos Base de dados: MEDLINE Assunto principal: Beta-Ciclodextrinas / Doença de Niemann-Pick Tipo C / Neuroblastoma Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: J Am Soc Mass Spectrom Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Suécia

Texto completo: 1 Coleções: 01-internacional Temas: Geral / Tipos_de_cancer / Outros_tipos Base de dados: MEDLINE Assunto principal: Beta-Ciclodextrinas / Doença de Niemann-Pick Tipo C / Neuroblastoma Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: J Am Soc Mass Spectrom Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Suécia