My talk will focus on developing mathematical and computational models that use the brain’s structural connectivity to predict the development of neurodegenerative diseases like Alzheimer’s. I will first describe our original proposal that Alzheimer's and other dementias are underpinned by misfolded pathologies that spread in the brain's structural connectome. This process can be...
Prion fibril assemblies exhibit a strong structural and dynamical heterogeneity that cannot be described by classical linear polymerization models.
Using single-assembly imaging and bulk kinetic measurements, we show that fibrillar and oligomeric subpopulations coexist and continuously exchange material through catalytically mediated processes. At the population level, this exchange...
Since 10 years, our lab has been developing a mechanistic model of the individual stress response based on the nucleo-shuttling of the ATM protein kinase. First, the stress triggers the monomerization of the ATM protein proportionally to the stress dose. Second, the ATM monomers diffuse to the nucleus to trigger the DNA repair pathways. Any delay caused by some environmental molecules or...
Alzheimer’s disease (AD) is a neurodegenerative disorder, with current therapies primarily focused on symptom management. Recent studies have proposed the Radiation-Induced ATM NucleoShuttling (RIANS) response as a mechanism that involves the formation of a perinuclear crown (PC) and may impair DNA repair.
We present a mathematical framework to investigate this process. First, an ordinary...
Prion proteins are notorious for their ability to induce neurodegenerative diseases by forming long fibrillar aggregates that accumulate in the brain. While the aggregation of these proteins and their fragmentation by oligomeric species are central to disease progression, the underlying mechanisms remain poorly understood. To better interpret experimental data, mathematical models have been...
We present and analyze an optimal control problem to model anti-inflammatory treatment strategies for Alzheimer’s disease, using a system of differential equations that captures interactions between ABeta-peptides, microglial cells, interleukins, and neurons. These interactions operate through mechanisms such as protein polymerization, inflammation processes, and neural stress responses. In...
The molecular chaperone Hsp104 is essential for the propagation of the yeast prion [PSI+], yet the precise mechanism by which it remodels prion aggregates remains contested. A leading alternative to the fragmentation model - in which Hsp104 internally severs amyloid fibers to generate new seeds - is the trimming hypothesis, which proposes that Hsp104 acts as a distinct enzymatic activity that...
In order to provide an explanation for the damped oscillations surprisingly observed in Prion depolymerization experiments, a bi-monomeric variant of the seminal Becker-Döring system is proposed. In this talk, we look in detail at the mechanisms leading to these oscillations. We characterize the dynamics of the system in different kinetic phases: from the initial phase of high amplitude...
The theme of this mini-symposium focuses on the mathematical modeling of protein dynamics in the context of neurodegenerative diseases such as Alzheimer’s, Creutzfeldt–Jakob, and Parkinson’s diseases. The proposed approaches span multiple biological scales, ranging from protein–protein interactions to cellular dynamics (protein–cell interactions), and up to tissue-level phenomena, including...
