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Monitoring Protein Aggregation Kinetics In Vivo using Automated Inclusion Counting in Caenorhabditis elegans

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Structural hormesis in protein aggregation: A minimal mechanistic model.

Abhishek Mallela¹, Santiago Schnell^1,2

¹Department of Mathematics, Dartmouth College, Hanover, NH, USA.

Journal of the Royal Society, Interface

|April 7, 2026

Summary

Protein aggregation inhibitors may not work as expected. Simple pathways can cause hormesis, where low inhibitor doses increase protein aggregation, while high doses decrease it, impacting neurodegenerative disease research.

Keywords:

biphasic dose–response hormesis inhibitor screening mathematical modelling ordinary differential equations protein aggregation reaction network topology

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Area of Science:

Biochemistry and Molecular Biology
Neuroscience
Computational Biology

Background:

Protein aggregation is central to neurodegenerative disease pathogenesis.
Inhibitors are typically screened assuming monotonic dose-responses.
Hormesis, a biphasic dose-response, is rarely considered in this context.

Purpose of the Study:

To investigate if simple protein aggregation pathways can intrinsically generate hormesis.
To explore the mechanistic basis of non-monotonic dose-responses for aggregation inhibitors.
To challenge the assumption of monotonic dose-response relationships in drug screening.

Main Methods:

Formulation of a minimal mechanistic model for protein aggregation.
Inclusion of a single inhibitor interacting sequentially with pathway intermediates.
Mathematical analysis and computational simulation of the model.

Main Results:

A robust non-monotonic (hormetic) dose-response was observed.
Low inhibitor concentrations paradoxically increased protein aggregate formation.
High inhibitor concentrations suppressed aggregate formation.

Conclusions:

Simple aggregation pathways can intrinsically generate hormesis.
The observed biphasic response is a structural property of the chemical network topology.
Full-range dose-response evaluation is crucial for effective inhibitor screening for neurodegenerative diseases.