Event Abstract

Unanswered role of cholesterol homeostasis in Parkinson’s disease

  • 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

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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

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