Principal Investigators

    Ernest Arenas


    Karolinska Institute

    Contact information of lead PI



    Title of project or programme

    Role of LXRs in midbrain dopamine neuron development and Parkinson’s disease

    Source of funding information

    The Swedish Brain Foundation

    Total sum awarded (Euro)

    € 139,282

    Start date of award


    Total duration of award in years



    Research Abstract

    Our group has identified nuclear receptors of the LXR family, LXR? and LXR?, as key regulators of midbrain dopaminergic (mDA) neurogenesis (Sacchetti et al, 2009, Cell stem cell). With the support of Hjärnfonden we identified endogenous brain LXR ligands as an entirely new family of very selective and potent regulators of neurogenesis and survival: While 24,25-EC selectively increases mDA neurogenesis, CA regulates both neurogenesis and survival of midbrain red nucleus neurons, and 3?,7?-diHCA selectively promotes motor neuron survival (Theofilopoulos et al., 2013 and 2014,
    Nature Chem. Biol and J. Clin. Invest.). More recently, with the support of Hjärnfonden, we began to elucidate the mechanism by which Lxr regulate mDA neurogenesis. Using a combined
    transcriptomic, cistromic and system biology approaches, we recently identified the transcription factor, Srebf1, as a direct target of Lxr required for mDA neurogenesis. However, many mechanistic and functional questions still remain. In the continuation of this project we propose to delve more
    into the mechanism of Srebf1-induced mDA neurogenesis and complete our ongoing analysis of the molecular mechanism by which LXRs are differentially activated in response to distinct endogenous LXR ligands. In addition of that we propose to investigate the role of Lxr/Srebf1 is A9 vs A10 mDA
    neurogenesis. We also plan to examine whether cholesterol metabolites and Lxr ligands are altered in the CSF of patients with diverse forms of Parkinson’s disease (PD) and examine whether such alterations may play a role in PD. Finally, we also propose to use Lxrs to: (1) Generate in vitro models of PD using PD-iPS cells and gene editing technology, in order to examine mechanisms of disease; and (2) Improve cell replacement strategies for PD using either stem cells or direct
    reprogramming. This project thus aims at providing further mechanistic insights into the function of LXR in development and disease and at contributing to the development of novel therapies for PD.

    Further information available at:

Types: Investments < €500k
Member States: Sweden
Diseases: N/A
Years: 2016
Database Categories: N/A
Database Tags: N/A

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