Principal Investigators

    Karsten Hiller


    Université du Luxembourg

    Contact information of lead PI



    Title of project or programme

    Modulation of tyrosine hydroxylase activity to control catecholamine synthesis and its effect on cellular metabolism - CORE

    Source of funding information


    Total sum awarded (Euro)

    € 584,000

    Start date of award


    Total duration of award in years


    The project/programme is most relevant to:

    Parkinson's disease & PD-related disorders


    Research Abstract

    Tyrosine hydroxylase (TH) is the rate limiting step for catecholamine (CA) biosynthesis including dopamine (DA). Decreased striatal DA levels caused by a loss of dopaminergic neurons in the substantia nigra are directly linked to Parkinson’s disease. We hypothesize that only modest increases in TH activity could compensate for the loss of many dopaminergic neurons (e.g. a 20% increase in activity may overcome a critical threshold of DA and may therefore compensate for a loss of dopaminergic neurons). On the other hand, CA intermediates and their degradation products are highly toxic to the cell. This is one of the reasons why TH is strictly regulated on several levels including transcription, protein stability, phosphorylation of specific residues in its regulatory domain and feedback inhibition by CAs. With the proposed research project, we intent to study how a modulation of TH can result in an increase in CA and DA production in whole human neuronal cells in culture. Moreover, we intend to determine the capacity limits of the metabolic flux through TH. By targeted profiling of CA metabolism and non-targeted profiling of central carbon metabolism, we will determine cellular effects caused by elevated TH activity. To reach our aims, we propose to express various defined variants of TH (differences on amino acid sequence level) in a human cellular neuronal cell culture system under the same genetic and regulatory background. Using this system, we will study CA metabolism and central carbon metabolism to investigate effects related to altered TH activity. Finally, the proposed system will allow for screening the activities of patient specific TH variants.

    Lay Summary

    Further information available at:

Types: Investments > €500k
Member States: Luxembourg
Diseases: Parkinson's disease & PD-related disorders
Years: 2016
Database Categories: N/A
Database Tags: N/A

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