Mutant huntingtin (mHtt) is a molecule prone to aggregation due to the presence of an abnormally long tandem of glutamines (polyQs). The aggregation dynamics of mHtt, and other prone-to-aggregation proteins, is modulated by a range of molecules and pathways. For example, autophagy and the proteasome clear out the cell from these toxic molecules. Although it is yet unknown whether aggregates or soluble species are the cause of the toxicity of these peptides containing polyQs, clearance of aggregates results in alleviation of their toxic effects.
We found by serendipity a mutation that enhances the aggregation pattern of a C. elegans strain which contains a transgene that induces the expression of a tandem of 40 glutamines (40Q) fused in frame with YFP (AM141). This strain shows an age-dependent aggregation pattern that can be easily followed using a dissecting microscope equipped with fluorescence. We sequenced by NGS means the whole genome of this strain, and we have identified a mutation in the unc-1/stomatin-like protein gene, vlt10, which enhances the aggregation phenotype of AM141. To verify the role of unc-1 in the dynamics of aggregation, we have introduced different unc-1 alleles within AM141 which confirmed that unc-1 is an enhancer of aggregation. We are currently working to find out the mechanism by which this gene modulates aggregation dynamics of polyQ-containing molecules.
- C. elegans
- protein aggregation