Polyglutamine aggregation proceeds by stochastic nucleation in the C. elegans nervous system
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.
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BibTeX
@misc{schijndel2026polyglutamine,
title = {{Polyglutamine aggregation proceeds by stochastic nucleation in the C. elegans nervous system}},
author = {Vera van Schijndel and Jorieke Tiggelaar and Myrthe S. E. Franken and Delano Remkes and Maithili Joshi and Deep Sandhu and Klaske Baars and Jesse D. F. de Graaf and Tessa Sinnige},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.29.755284},
url = {https://www.biorxiv.org/content/10.64898/2026.09.29.755284v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Polyglutamine aggregation proceeds by stochastic nucleation in the C. elegans nervous system
AU - Vera van Schijndel
AU - Jorieke Tiggelaar
AU - Myrthe S. E. Franken
AU - Delano Remkes
AU - Maithili Joshi
AU - Deep Sandhu
AU - Klaske Baars
AU - Jesse D. F. de Graaf
AU - Tessa Sinnige
PY - 2026
DA - 2026/09/29
PB - bioRxiv
DO - 10.64898/2026.09.29.755284
UR - https://www.biorxiv.org/content/10.64898/2026.09.29.755284v1
AB - 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.
SN - 2692-8205
ER -