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

Elena Righetti^{1, 2}, Alice Antonello³, Luca Marchetti^{1, 2}, Enrico Domenici^{1, 2} and Federico Reali^1*

• ¹Fondazione The Microsoft Research - University of Trento Centre for Computational and Systems Biology, Italy
• ²Department of Cellular, Computational and Integrated Biology, University of Trento, Italy
• ³Department of Mathematics and Geosciences, University of Trieste, Italy

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, 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.