A28 Steroid hormone signaling may regulate homeostasis of polyq-containing proteins in c. elegans

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Abstract

Toxicity induced by proteins containing polyglutamines (polyQs) is the cause of different neurodegenerative diseases, such as Huntington’s disease (HD). Mutant huntingtin (mHtt) is prone to aggregation, due to an abnormally long polyQ at the N-terminal region, which is believed to cause aggregation of other molecules, and contributes to the toxicity in patients of HD. Despite HD is a monogenic disease, there may be genes that modify the dynamics of mHtt aggregation and clearance, and therefore may modulate the onset and the progression of the disease in HD patients.

To look for modifier genes that modulate the dynamics of aggregation of polyQ-containing proteins, we performed random chemical mutagenesis in Caenorhabditis elegans (C. elegans) worms that expresses 40 glutamines (40Q) fused in frame with YFP in muscle cells. 40Q::YFP aggregates in an age-dependent fashion, producing inclusion bodies that can be easily followed using a dissecting microscope equipped with fluorescence.

We isolated a mutation that enhances the aggregation phenotype of 40Q::YFP worms. We identified the responsible mutation, vlt10, in the unc-1/Stomatin like protein gene by means of NGS. To verify the role of unc-1(vlt10) in the dynamics of aggregation, we have analysed different unc-1 mutations (e719, e1598) which confirmed that unc-1 is a modulator of aggregation. In addition, the product of unc-1 (UNC-1) works in nervous system to regulate protein homeostasis in muscle cells, suggesting that UNC-1 acts non-cell autonomously.

To shed light into potential mechanisms of protein homeostasis modulation by unc-1, we performed genetic interaction studies. Among genes and pathways tested, we observed that the unc-1 phenotype is rescued by loss of function of ssu-1, a gene encoding a sulfotransferase enzyme which expression is restricted to the ASJ neurons. It is believed that SSU-1 adds sulphur to hormones produced by ASJ, to facilitate distribution among tissues by hormonal signalling. A steroid nuclear receptor, NHR-1, has been related with hormonal signalling from SSU-1. So we have analysed the ablation of this receptor in unc-1 mutant background to elucidate the mechanism.

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