Unanswered role of cholesterol homeostasis in Parkinson’s disease
Maria
J.
Nunes1, 2,
Ines
Caria1, 2,
Andreia
N.
Carvalho1, 2,
Daniela
Costa1, 2,
Margarida
Castro-Caldas1, 3,
Maria
J.
Gama1, 2,
Elsa
Rodrigues1, 2 and
Jorge
L.
Ruas1, 4*
-
1
Research Institute for Medicines (iMed.ULisboa), Portugal
-
2
Faculdade de Farmácia, Universidade de Lisboa, Portugal
-
3
Faculdade de Ciências e Tecnologia da Universidade Nova de Lisboa, Portugal
-
4
Department of Physiology and Pharmacology, Karolinska Institutet, Sweden
Cholesterol has a key role in neuronal function and alterations in brain cholesterol homeostasis correlate with neurodegeneration. While disruptions in cholesterol homeostasis have been clearly associated with neurodegenerative disorders such as Alzheimer’s and Huntington’s disease, the role of cholesterol in Parkinson’s disease (PD) remains controversial. To address this question, we started by characterizing the changes in cholesterol homeostasis in the brain of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. Our results suggest that the levels of the active form of the major regulator of cholesterol synthesis, the sterol regulatory element-binding protein (SREBP) 2 protein are increased in the midbrain of mice treated for 3 hours with MPTP (40mg/Kg, i.p.), concomitantly with an increase in the neuronal specific cholesterol 24- hydroxylase protein levels. However, the observed increase in the cleaved form of SREBP2, does not seem to produce a classic response in its target genes, since some of its canonical downstream targets, such as hydroxymethylglutaryl-CoA synthase, appear to be downregulated. To further evaluate this effect, we treated neuroblastoma and primary cultures of mice neurons with the MPTP toxic metabolite 1-methyl-4-phenylpyridinium (MPP+) and determined SREBP2 cleavage and activation, and intracellular cholesterol localization and levels. Our results show a deregulation of cholesterol homeostasis in the context of PD, which may contribute to the neurodegeneration associated with this disease.
Acknowledgements
This work was supported by FEDER and national funds from Fundação para a Ciência e Tecnologia (FCT) (PTDC/MEDFSL/30104/2017, UID/DTP/04138/2013 and fellowships SFRH/BPD/95855/2013 to MJN and SFRH/BPD/98023/2013 to ANC).
Keywords:
brain cholesterol,
Parkinson ’s disease,
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP),
sterol regulatory element-binding protein 2 (SREBP2),
neurodegeneration
Conference:
XVI Meeting of the Portuguese Society for Neuroscience (SPN2019), Lisboa, Portugal, 30 May - 1 Jun, 2019.
Presentation Type:
Poster presentation
Topic:
Cellular and Molecular Neurosciences
Citation:
Nunes
MJ,
Caria
I,
Carvalho
AN,
Costa
D,
Castro-Caldas
M,
Gama
MJ,
Rodrigues
E and
Ruas
JL
(2019). Unanswered role of cholesterol homeostasis in Parkinson’s disease.
Front. Cell. Neurosci.
Conference Abstract:
XVI Meeting of the Portuguese Society for Neuroscience (SPN2019).
doi: 10.3389/conf.fncel.2019.01.00024
Copyright:
The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers.
They are made available through the Frontiers publishing platform as a service to conference organizers and presenters.
The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated.
Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed.
For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions.
Received:
16 Apr 2019;
Published Online:
27 Sep 2019.
*
Correspondence:
PhD. Jorge L Ruas, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Stockholm, SE-104 35, Sweden, jorge.ruas@ki.se