Mechanistic models of α-synuclein homeostasis for Parkinson's disease: A blueprint for therapeutic intervention

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide, yet there is no disease-modifying therapy up to this date. The biological complexity underlying PD hampers the investigation of the principal contributors to its pathogenesis. In this context, mechanistic models grounded in molecular-level knowledge provide virtual labs to uncover the primary events triggering PD onset and progression and suggest promising therapeutic targets. Multiple modeling efforts in PD research have focused on the pathological role of α-synuclein (αsyn), a presynaptic protein that emerges from the intricate molecular network as a crucial driver of neurodegeneration. Here, we collect the advances in mathematical modeling of αsyn homeostasis, focusing on aggregation and degradation pathways, and discussing potential modeling improvements and possible implications in PD therapeutic strategy design.

Systems biology platform for efficient development and translation of multitargeted therapeutics

“…In addition, utilizing systems biology analysis to identify genetic mutations or epigenetic changes linked to disease to help define patient subpopulations that are more likely to response to treatment is crucial. For example, understanding both genetically defined segments of Parkinson (such as GBA, LRKK2 and alphasynuclein) and underlying MOD that may be overlapping across these segments, and potentially shared with other neurodegenerative diseases allows for optimal patient selection in POC trials focused on selected biomarkers relevant to the segment, as well as a longer term strategy of advancing combinations that may be beneficial across diseases with shared underlying biology (Merchant et al, 2019;Bloomingdale et al, 2022;Righetti et al, 2022).…”

Advancing precision medicine therapeutics for Parkinson’s utilizing a shared quantitative systems pharmacology model and framework

“…In ALS, an ALS-SOD1 QSP model which incorporates SOD-1 specific biology and neurofilament light (NFL) biomarker, was developed and used to predict the response to treatment on Tofersen allowing for optimization of dose and treatment protocol (Paris et al, 2022;Biogen, 2023). Moreover, there has been much progress on important QSP model components and building blocks for PD that can facilitate and accelerate the build-up and delivery of QSP application to translational questions, such as an alphasynuclein model (Righetti et al, 2022). In one mechanistic model, investigators incorporated alpha-synuclein dynamics and other mediators that drive accumulation during disease and potential reduction on treatment.…”