Project number 17

Effect of polyQ expansions on phase transitions of proteins involved in neurodegeneration

PolyQ expansions in ataxin-2 and in the androgen receptor (AR) are associated with different forms of neurodegeneration. While expansion in the AR cause Kennedy’s disease, intermediate expansions in ataxin-2 are a risk factor for amyotrophic lateral sclerosis (ALS) and longer expansions cause spinocerebellar ataxia.
Recent evidence indicates that polyQ regions not only form amyloids, they also take part in the formation of liquid droplets, so called “membraneless organelles”, both in vitro and in vivo. PolyQ regions often reside in intrinsically disordered low complexity regions (LCRs) of proteins, the multi-valent interactions of which underlies the formation of such highly interconnected, dynamic proteinaceous phases that can organize cytosolic and nuclear material in the cell. Understanding the exact biochemical background of the interplay between polyQ regions and phase transitions could shed new light on neurodegeneration.
The physicochemical consequences of the repeats will be investigated in the Tompa lab using phase-contrast microscopy, viscosity measurements and FRAP. The structural state of the proteins will be studied using CD spectroscopy, fluorescence spectroscopy (FRET), cross-linking, mass-spectrometry and NMR spectroscopy.
The biological consequences of the different repeat lengths and of modifiers will be studied in the Van Den Bosch lab both in vitro and in vivo. In vitro models include cell lines as well as induced pluripotent stem cell lines (iPSCs) from patients with different repeat lengths. As in vivo model, we will use Drosophila.
Altogether, both approaches will provide further insights into the effect of the polyQ repeats on the structural and biological behavior of the different proteins.
This proposal is a continuation of an ongoing collaboration (Boeynaems, et al., submitted)

neurodegeneration, Motor neuron, PolyQ disease, Phase separation, Low complexity domains

Peter Tompa, VIB Structural Biology Research Center, VUB, Brussels
Ludo Van Den Bosch, VIB Vesalius Research Center, KU Leuven, Leuven