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

TL;DR

This paper reviews mechanistic models of alpha-synuclein homeostasis in Parkinson's disease, highlighting their role in understanding disease progression and guiding therapeutic development.

Contribution

It compiles and analyzes recent mathematical models of alpha-synuclein dynamics, proposing improvements and exploring implications for PD treatment strategies.

Findings

Models elucidate alpha-synuclein aggregation pathways

Insights into degradation mechanisms suggest therapeutic targets

Frameworks for designing disease-modifying interventions

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 $\alpha$-synuclein ($\alpha$syn), 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 $\alpha$syn homeostasis, focusing on aggregation and degradation pathways, and discussing potential modeling improvements and possible implications in PD therapeutic strategy design.