Abstract / Summary
Fibrillar protein aggregation is the hallmark of a wide variety of neurodegenerative diseases. It is still poorly understood how soluble proteins transition to fibrillar aggregates, in particular within the complex environment of cells and tissues. Here, we employ the nematode Caenorhabditis elegans to elucidate the molecular mechanisms of polyglutamine aggregation in the nervous system of a multicellular animal. By using fluorescence microscopy in combination with mathematical modelling, we find that polyglutamine aggregation occurs by stochastic nucleation in individual neurons, at a rate that is of the same order of magnitude as previously determined for muscle cells. The J-protein DNAJB6 strongly suppresses polyglutamine aggregation in both tissues, consistent with a mechanism in which aggregation is limited by primary nucleation. We confirm that the same mechanism holds true for a construct including the disease-relevant flanking regions of Huntingtin exon 1. Altogether, our data reveal that polyglutamine aggregation occurs spontaneously and largely independent of the cellular context.