SH007 - Polyglutamine aggregation occurs by stochastic nucleation in Caenorhabditis elegans neurons

SH007

Polyglutamine aggregation occurs by stochastic nucleation in Caenorhabditis elegans neurons

V. van Schijndel¹, J. Tiggelaar¹, M. Franken¹, K. Baars¹, D. Remkes¹, A. den Outer¹, J. Meulenbrugge¹, J. de Graaf¹, M. Floor¹, M. Couperus¹, T. Sinnige^1,*

¹Utrecht University, Utrecht, Netherlands

Rationale: 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.

Methods: Here, we use the nematode Caenorhabditis elegans to elucidate the molecular mechanisms of polyglutamine aggregation, which is related to Huntington's disease, in the nervous system of a multicellular animal. We employ fluorescence microscopy in combination with mathematical modelling to establish the mechanism of aggregation, and we investigate the role of protein homeostasis by using RNA interference against selected genes.

Results: 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 [1]. However, we do find tissue-specific differences in protein homeostasis. The chaperonin TRiC/CCT influences polyglutamine aggregation in muscle cells, but not in neurons. Overexpression of the J-protein DNAJB6 effectively suppresses polyglutamine aggregation in both tissues, in agreement with the aggregation process being limited by primary nucleation.

Conclusions: Altogether, we here develop a mechanistic framework to quantitatively analyse the progression of protein aggregation in the nervous system of a multicellular animal model. We anticipate that our approach can be exploited in the future to understand the aggregation of other disease-related proteins, which may undergo more complex behaviour such as cell-to-cell spreading and modulation by aggregate clearance.

References: 1 Sinnige T et al. (2021) Proc Natl Acad Sci USA 118 (11), e2021888118

Disclosure of Interest: None declared