Work

Structural hormesis in protein aggregation: A minimal mechanistic model

Year: 2026

Type: article

Abstract: Protein aggregation underlies the pathogenesis of many neurodegenerative diseases, and inhibitors are often assumed to elicit monotonic dose-responses. We ask whether simple aggregation pathways can intrinsically generate hormesis-a biphasic profile with low-dose stimulation and high-dose inhibition. We formulate a minimal mechanistic model in which a single inhibitor interacts sequentially with pathway intermediates. Analysis and simulation show a robust non-monotonic response: low inhibitor doses increase aggregate formation, whereas high doses suppress it. We prove that this profile is structural-arising from chemical network topology rather than tuned kinetic parameters. The mechanism rationalizes pro-aggregating effects at low doses and underscores the need for full-range dose-response evaluation in inhibitor screening.

Source: Journal of The Royal Society Interface

DOI: 10.1098/rsif.2025.1037

Authors: Abhishek Mallela, Santiago Schnell

Institution: Dartmouth College

Language: English

Topic: Alzheimer's disease research and treatments

Subfield: Physiology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Funder: Dartmouth College