WP1: Intracellular localisation and protein transport

WP2: Protein aggregation and degradation

WP3: Experimental therapeutics targeting PolyQ diseases

Both huntingtin and ataxin-3 are mainly cytoplasmic proteins. In patients, however, protein aggregates are forming inside of the nucleus. Compelling evidence indicate that the nuclear localization of the affected protein is of critical importance for the pathogenesis in these diseases highlighting the nuclear transport as a promising target for therapeutic intervention.
We aim to apply novel methods in order to understand how normal and expanded polyQ proteins can pass through the nuclear membrane and which proteins are involved in the nuclear transport of ataxin-3. We also aim to identify small molecules able to control this transport.

Protein aggregation is a hallmark of multiple neurodegenerative disorders. Yet the mechanisms through which polyQ proteins accumulate and exert their toxic effects remain unknown. However, both the reduction of aggregation and improvement of polyQ protein degradation are of special therapeutical importance. Accordingly, we aim to understand why polyQ- containing proteins aggregate, by which mechanisms they are degraded via the ubiquitin-proteasome system and how they can specifically targeted for protein degradation. We will address the last question from two directions both via the ubiquitin-proteasome system and via autophagy.

At the moment, there are no causal treatments available for polyQ diseases. Therefore, novel therapeutic strategies need to be developed. We aim to develop strategies targeting in an allelspecific manner the expression of the affected gene in vivo, to restore the protein homeostasis by targeting the protein folding machinery, and to apply established bioassays to identify modulators of HD pathogenesis. These analyses will be done in vitro and in vivo by using well established cellular systems, recently developed transgenic mouse lines and drosophila as a cost-efficient platform both for screening and validation of promising compounds in vivo.