NPC1-like phenotype, with intracellular cholesterol accumulation and altered mTORC1 signaling in models of Parkinson's disease
| Main Author: | |
|---|---|
| Publication Date: | 2024 |
| Other Authors: | , , , , , , , , , |
| Format: | Article |
| Language: | eng |
| Source: | Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) |
| Download full: | http://hdl.handle.net/10362/163059 |
Summary: | Funding Information: The work was supported by FEDER/Programa Operacional Regional de Lisboa – Lisboa 2020 (LISBOA-01-0145-FEDER-030104) and by National funds from Fundação para a Ciência e a Tecnologia (PTDC/MEDFSL/30104/2017), and by the Swedish Research Council. Publisher Copyright: © 2023 The Authors |
| id |
RCAP_4ee05eafd7f94d0abcd21c051e661ae7 |
|---|---|
| oai_identifier_str |
oai:run.unl.pt:10362/163059 |
| network_acronym_str |
RCAP |
| network_name_str |
Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) |
| repository_id_str |
https://opendoar.ac.uk/repository/7160 |
| spelling |
NPC1-like phenotype, with intracellular cholesterol accumulation and altered mTORC1 signaling in models of Parkinson's diseaseBrain cholesterol metabolismLysosomesMitochondria dysfunctionNPC1Parkinson's diseaseMolecular MedicineMolecular BiologySDG 3 - Good Health and Well-beingFunding Information: The work was supported by FEDER/Programa Operacional Regional de Lisboa – Lisboa 2020 (LISBOA-01-0145-FEDER-030104) and by National funds from Fundação para a Ciência e a Tecnologia (PTDC/MEDFSL/30104/2017), and by the Swedish Research Council. Publisher Copyright: © 2023 The AuthorsDisruption of brain cholesterol homeostasis has been implicated in neurodegeneration. Nevertheless, the role of cholesterol in Parkinson's Disease (PD) remains unclear. We have used N2a mouse neuroblastoma cells and primary cultures of mouse neurons and 1-methyl-4-phenylpyridinium (MPP+), a known mitochondrial complex I inhibitor and the toxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), known to trigger a cascade of events associated with PD neuropathological features. Simultaneously, we utilized other mitochondrial toxins, including antimycin A, oligomycin, and carbonyl cyanide chlorophenylhydrazone. MPP+ treatment resulted in elevated levels of total cholesterol and in a Niemann Pick type C1 (NPC1)-like phenotype characterized by accumulation of cholesterol in lysosomes. Interestingly, NPC1 mRNA levels were specifically reduced by MPP+. The decrease in NPC1 levels was also seen in midbrain and striatum from MPTP-treated mice and in primary cultures of neurons treated with MPP+. Together with the MPP+-dependent increase in intracellular cholesterol levels in N2a cells, we observed an increase in 5′ adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and a concomitant increase in the phosphorylated levels of mammalian target of rapamycin (mTOR). NPC1 knockout delayed cell death induced by acute mitochondrial damage, suggesting that transient cholesterol accumulation in lysosomes could be a protective mechanism against MPTP/MPP+ insult. Interestingly, we observed a negative correlation between NPC1 protein levels and disease stage, in human PD brain samples. In summary, MPP+ decreases NPC1 levels, elevates lysosomal cholesterol accumulation and alters mTOR signaling, adding to the existing notion that PD may rise from alterations in mitochondrial-lysosomal communication.DCV - Departamento de Ciências da VidaUCIBIO - Applied Molecular Biosciences UnitRUNCaria, InêsNunes, Maria JoãoCiraci, VivianaCarvalho, Andreia NevesRanito, CatarinaSantos, Susana G.Gama, Maria JoãoCastro-Caldas, MargaridaRodrigues, Cecília M. P.Ruas, Jorge L.Rodrigues, Elsa2024-02-02T23:40:54Z2024-022024-02-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article16application/pdfhttp://hdl.handle.net/10362/163059eng0925-4439PURE: 81715012https://doi.org/10.1016/j.bbadis.2023.166980info:eu-repo/semantics/openAccessreponame:Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)instname:FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologiainstacron:RCAAP2024-05-22T18:17:59Zoai:run.unl.pt:10362/163059Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireinfo@rcaap.ptopendoar:https://opendoar.ac.uk/repository/71602025-05-28T17:48:23.717575Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) - FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologiafalse |
| dc.title.none.fl_str_mv |
NPC1-like phenotype, with intracellular cholesterol accumulation and altered mTORC1 signaling in models of Parkinson's disease |
| title |
NPC1-like phenotype, with intracellular cholesterol accumulation and altered mTORC1 signaling in models of Parkinson's disease |
| spellingShingle |
NPC1-like phenotype, with intracellular cholesterol accumulation and altered mTORC1 signaling in models of Parkinson's disease Caria, Inês Brain cholesterol metabolism Lysosomes Mitochondria dysfunction NPC1 Parkinson's disease Molecular Medicine Molecular Biology SDG 3 - Good Health and Well-being |
| title_short |
NPC1-like phenotype, with intracellular cholesterol accumulation and altered mTORC1 signaling in models of Parkinson's disease |
| title_full |
NPC1-like phenotype, with intracellular cholesterol accumulation and altered mTORC1 signaling in models of Parkinson's disease |
| title_fullStr |
NPC1-like phenotype, with intracellular cholesterol accumulation and altered mTORC1 signaling in models of Parkinson's disease |
| title_full_unstemmed |
NPC1-like phenotype, with intracellular cholesterol accumulation and altered mTORC1 signaling in models of Parkinson's disease |
| title_sort |
NPC1-like phenotype, with intracellular cholesterol accumulation and altered mTORC1 signaling in models of Parkinson's disease |
| author |
Caria, Inês |
| author_facet |
Caria, Inês Nunes, Maria João Ciraci, Viviana Carvalho, Andreia Neves Ranito, Catarina Santos, Susana G. Gama, Maria João Castro-Caldas, Margarida Rodrigues, Cecília M. P. Ruas, Jorge L. Rodrigues, Elsa |
| author_role |
author |
| author2 |
Nunes, Maria João Ciraci, Viviana Carvalho, Andreia Neves Ranito, Catarina Santos, Susana G. Gama, Maria João Castro-Caldas, Margarida Rodrigues, Cecília M. P. Ruas, Jorge L. Rodrigues, Elsa |
| author2_role |
author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
DCV - Departamento de Ciências da Vida UCIBIO - Applied Molecular Biosciences Unit RUN |
| dc.contributor.author.fl_str_mv |
Caria, Inês Nunes, Maria João Ciraci, Viviana Carvalho, Andreia Neves Ranito, Catarina Santos, Susana G. Gama, Maria João Castro-Caldas, Margarida Rodrigues, Cecília M. P. Ruas, Jorge L. Rodrigues, Elsa |
| dc.subject.por.fl_str_mv |
Brain cholesterol metabolism Lysosomes Mitochondria dysfunction NPC1 Parkinson's disease Molecular Medicine Molecular Biology SDG 3 - Good Health and Well-being |
| topic |
Brain cholesterol metabolism Lysosomes Mitochondria dysfunction NPC1 Parkinson's disease Molecular Medicine Molecular Biology SDG 3 - Good Health and Well-being |
| description |
Funding Information: The work was supported by FEDER/Programa Operacional Regional de Lisboa – Lisboa 2020 (LISBOA-01-0145-FEDER-030104) and by National funds from Fundação para a Ciência e a Tecnologia (PTDC/MEDFSL/30104/2017), and by the Swedish Research Council. Publisher Copyright: © 2023 The Authors |
| publishDate |
2024 |
| dc.date.none.fl_str_mv |
2024-02-02T23:40:54Z 2024-02 2024-02-01T00:00:00Z |
| dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
| dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| status_str |
publishedVersion |
| dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10362/163059 |
| url |
http://hdl.handle.net/10362/163059 |
| dc.language.iso.fl_str_mv |
eng |
| language |
eng |
| dc.relation.none.fl_str_mv |
0925-4439 PURE: 81715012 https://doi.org/10.1016/j.bbadis.2023.166980 |
| dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
| eu_rights_str_mv |
openAccess |
| dc.format.none.fl_str_mv |
16 application/pdf |
| dc.source.none.fl_str_mv |
reponame:Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) instname:FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologia instacron:RCAAP |
| instname_str |
FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologia |
| instacron_str |
RCAAP |
| institution |
RCAAP |
| reponame_str |
Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) |
| collection |
Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) |
| repository.name.fl_str_mv |
Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) - FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologia |
| repository.mail.fl_str_mv |
info@rcaap.pt |
| _version_ |
1833596979276414976 |