Changes in Liver Lipidomic Profile in G2019S- LRRK2 Mouse Model of Parkinson's Disease

Yaiza Corral Nieto; Sokhna M S Yakhine-Diop; Paula Moreno-Cruz; Laura Manrique García; Amanda Gabrielly Pereira; José A Morales-García; Mireia Niso-Santano; Rosa A González-Polo; Elisabet Uribe-Carretero; Sylvère Durand; Maria Chiara Maiuri; Marta Paredes-Barquero; Eva Alegre-Cortés; Saray Canales-Cortés; Adolfo López de Munain; Jordi Pérez-Tur; Ana Pérez-Castillo; Guido Kroemer; José M Fuentes; José M Bravo-San Pedro

doi:10.3390/cells12050806

Changes in Liver Lipidomic Profile in G2019S- LRRK2 Mouse Model of Parkinson's Disease

Cells. 2023 Mar 4;12(5):806. doi: 10.3390/cells12050806.

Authors

Yaiza Corral Nieto¹, Sokhna M S Yakhine-Diop^{2

3

4}, Paula Moreno-Cruz¹, Laura Manrique García¹, Amanda Gabrielly Pereira¹, José A Morales-García^{3

5

6}, Mireia Niso-Santano^{2

3

4}, Rosa A González-Polo^{2

3

4}, Elisabet Uribe-Carretero^{2

3

4}, Sylvère Durand⁷, Maria Chiara Maiuri^{7

8}, Marta Paredes-Barquero^{2

4}, Eva Alegre-Cortés^{2

4}, Saray Canales-Cortés^{2

4}, Adolfo López de Munain^{3

9

10

11

12}, Jordi Pérez-Tur^{3

13

14}, Ana Pérez-Castillo^{3

6}, Guido Kroemer^{7

8

15}, José M Fuentes^{2

3

4}, José M Bravo-San Pedro^{1

3}

Affiliations

¹ Departamento de Fisiología, Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain.
² Departamento de Bioquímica y Biología Molecular y Genética, Facultad de Enfermería y Terapia Ocupacional, Universidad de Extremadura, 10003 Cáceres, Spain.
³ Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas-Instituto de Salud Carlos III (CIBER-CIBERNED-ISCIII), 28029 Madrid, Spain.
⁴ Instituto Universitario de Investigación Biosanitaria de Extremadura (INUBE), 10003 Cáceres, Spain.
⁵ Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), 28029 Madrid, Spain.
⁶ Departamento de Biología Celular, Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain.
⁷ Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France.
⁸ Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Inserm U1138, Université Paris Cité, Sorbonne Université, 75006 Paris, France.
⁹ Neuroscience Area of Biodonostia Health Research Institute, Donostia University Hospital, 20014 San Sebastián, Spain.
¹⁰ Department of Neurology, Donostia University Hospital, OSAKIDETZA, 20014 San Sebastian, Spain.
¹¹ Ilundain Foundation, 20018 San Sebastian, Spain.
¹² Department of Neurosciences, University of the Basque Country UPV-EHU, 20014 San Sebastián, Spain.
¹³ Instituto de Biomedicina de Valencia-CSIC, Unidad de Genética Molecular, 46010 Valencia, Spain.
¹⁴ Unidad Mixta de Genética y Neurología, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain.
¹⁵ Institut du Cancer Paris CARPEM, Department of Biology, Hopital Européen Georges Pompidou, AP-HP, 75015 Paris, France.

Abstract

The identification of Parkinson's disease (PD) biomarkers has become a main goal for the diagnosis of this neurodegenerative disorder. PD has not only been intrinsically related to neurological problems, but also to a series of alterations in peripheral metabolism. The purpose of this study was to identify metabolic changes in the liver in mouse models of PD with the scope of finding new peripheral biomarkers for PD diagnosis. To achieve this goal, we used mass spectrometry technology to determine the complete metabolomic profile of liver and striatal tissue samples from WT mice, 6-hydroxydopamine-treated mice (idiopathic model) and mice affected by the G2019S-LRRK2 mutation in LRRK2/PARK8 gene (genetic model). This analysis revealed that the metabolism of carbohydrates, nucleotides and nucleosides was similarly altered in the liver from the two PD mouse models. However, long-chain fatty acids, phosphatidylcholine and other related lipid metabolites were only altered in hepatocytes from G2019S-LRRK2 mice. In summary, these results reveal specific differences, mainly in lipid metabolism, between idiopathic and genetic PD models in peripheral tissues and open up new possibilities to better understand the etiology of this neurological disorder.

Keywords: LRRK2; Parkinson; lipids; liver; metabolome; neurodegeneration.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Biomarkers
Disease Models, Animal
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics
Lipidomics
Liver / metabolism
Metabolomics
Mice
Parkinson Disease* / metabolism

Substances

Biomarkers
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
Lrrk2 protein, mouse

Grants and funding

This research was supported by “Instituto de Salud Carlos III”, “Fondo de Investigaciones Sanitarias” (PI15/0034), “CIBERNED-ISCIII” (CB06/05/0041 and 2015/03), and partially supported by “European Regional Development Fund (ERDF)” from the European Union. J.M.B.-S.P. is funded by “Ramon y Cajal Program” (RYC-2018-025099-I) and supported by Spain’s Ministerio de Ciencia e Innovación (PID2019-108827RA-I00). Y.C.N. and L.M.G. are funded by Community of Madrid (CT5/21/PEJ-2020-TL/BMD-17685 and CT36/22-41-UCM-INV respectively). S.M.S.Y.-D. was supported by CIBERNED-ISCIII. P.M.-C. is funded by the MINECO Spanish Ministry (FPI grant, PRE2020-092668). M.N.-S. was funded by “Ramon y Cajal Program” (RYC-2016-20883). E.U.-C. and S.C.-C. were supported by an FPU predoctoral fellowship (FPU16/00684) and FPU19/04435), respectively, from “Ministerio de Educación, Cultura y Deporte”. M.P-B was funded by a University of Extremadura fellowship. E.A-C was supported by a Grant (IB18048) from Junta de Extremadura, Spain. J.M.F. received research support from the “Instituto de Salud Carlos III”; “Fondo de Investigaciones Sanitarias” (PI15/0034) and CIBERNED-ISCIII (CB06/05/0041 and 2015/03). A.P.-C. was supported by MINECO (SAF2014-52940-R and SAF2017-85199-P). J.P.-T. received funding from CIBERNED-ISCIII (CB06/05/1123 and 2015/03). G.K. is supported by the Ligue contre le Cancer (équipe labellisée); Agence National de la Recherche (ANR)—Projets blancs; ANR under the frame of E-Rare-2, the ERANet for Research on Rare Diseases; AMMICa US/CNRS UMS3655; Association pour la recherche sur le cancer (ARC); Association “Le Cancer du Sein, Parlons-en!”; Cancéropôle Ile de-France; Chancelerie des universités de Paris (Legs Poix), Fondation pour la Recherche Médicale (FRM); a donation by Elior; European Research Area Network on Cardiovascular Diseases (ERA-CVD, MINOTAUR); Gustave Roussy Odyssea, the European Union Horizon 2020 Project Oncobiome; Fondation Carrefour; High-end Foreign Expert Program in China (GDW20171100085), Institut National du Cancer (INCa); Inserm (HTE); Institut Universitaire de France; LeDucq Foundation; the LabEx Immuno-Oncology (ANR-18-IDEX-0001); the RHU Torino Lumière; the Seerave Foundation; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); and the SIRIC Cancer Research and Personalized Medicine (CARPEM).