Work

Polyglutamine aggregation in the C. elegans nervous system is driven by stochastic nucleation events

Year: 2026

Type: preprint

Abstract: 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 independently of the cellular context, rather than as a consequence of ageing and the associated decline in protein homeostasis.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.09.29.755284