The maintenance of protein homeostasis is essential for organism survival. Misfolded proteins may alter this balance because they are susceptible to form toxic aggregates. This pathological context is common in many neurodegenerative disorders such as Huntington disease, Alzheimer, Parkinson and ALS. Aggregation dynamics may be monitored in vivo using C. elegans that expresses prone-to-aggregation molecules, tagged with fluorescent proteins. We did a random mutagenesis screening to isolate modifier genes that modulates protein aggregation of polyglutamines (polyQs). We isolated a mutant allele (
vlt10), of the electrical synapse modulator
unc-1/Stomatin Like protein 3. This allele enhances polyQ aggregation in muscle cells in a neuron-specific manner. We show that
vlt10 induces an excess of neurohormonal signalling from the cytosolic sulfotransferase SSU-1, which functions in ASJ neurons. This hormonal signal targets into the nuclear hormone receptor 1 (NHR-1), which appear to regulate genes of the lipid metabolism, which in turns modulate polyQ aggregation. Additionally, we have identified an opposite modulator role from another hormonal pathway which leads to DAF-12. Our findings suggest that steroid hormones induce changes in fat metabolism that impact over protein homeostasis. Some components of this pathways are enzymes or receptors susceptible to be modulated by compounds, and therefore they are potential druggable targets to treat neurodegenerative diseases.