Ph.D. Projects


Molecular mechanisms of polyQ Atro glial toxicity
We have generated several different Drosophila models of DRPLA by expressing wt and polyQ forms of human At-1 and of Drosophila Atro. In this context we describe a striking reduction in fly viability when polyQ Atrophins are expressed in the glia rather than neurones. Importantly this phenotype is shared by a Drosophila model of SCA3. This raises the possibility that polyQ proteins affect the whole nervous system through a specific role in the glia, which is surprising since most studies have until now focused on polyQ toxicity in neurones.
The student will use the existing Drosophila models to:

  

  • address specific mechanisms of glial toxicity also through the use of pharmacological tools by testing

     

    • whether the effect is due to glial cell loss
    • whether the observed autophagic modifications are causative of lifespan shortening
    • whether glutamate excitotoxicity may be involved in glial toxicity
    • whether the glial toxicity is a systemic effect or is due to a specific sub-population

     

  • conduct an unbiased genetic screen to identify by random gene overexpression or by RNAi, mutations that modify the viability of DRPLA fly models. 

 

In addition the student will generate a new Drosophila model that expresses polyQ Atrophin directly under a glial promoter, which will allow studying non autonomous effect in neurones. This aims at identifying glia-neurone interaction mechanisms that are crucial in controlling lifespan.
These studies will assess whether a larger part of the nervous system than the degenerated neurones is affected through glial dysfunction.