# The α-synuclein proteostasis network and its translational applications in Parkinson’s disease

## TL;DR

The paper maps the α-synuclein proteostasis network in Parkinson’s disease brains to identify potential therapeutic targets and drug repurposing opportunities.

## Contribution

The study introduces a proteostasis activity score (PAS) and a computational framework for identifying actionable targets in Parkinson’s disease.

## Key findings

- PAS stratifies Parkinson’s disease brains and correlates with age at death and regional vulnerability.
- Network analysis identifies six actionable targets and 28 approved drugs that promote α-synuclein clearance.
- A digital twin model of the α-synuclein proteostasis network enables drug repurposing and target prioritization.

## Abstract

As proteostasis collapse drives many neurodegenerative disorders, it is important to develop quantitative frameworks for its assessment. Here, we map the α-synuclein (α-Syn) proteostasis network in the human substantia nigra by integrating transcriptomic and proteomic data. We thus derive a proteostasis activity score (PAS) that captures the balance between aggregation-promoting and aggregation-attenuating pathways. PAS stratifies Parkinson’s disease (PD) vs. control brains, correlates with age at death, and predicts regional and peripheral vulnerability to pathology. Network influence analyses highlight previously unrecognized master regulators, six actionable targets, and 28 approved drugs that shift the network toward α-syn clearance. Our work provides a generalizable blueprint for decoding proteostasis landscapes and accelerating therapeutic discovery across protein-misfolding diseases with potential applications in precision medicine.

Parkinson’s disease (PD) is a debilitating neurodegenerative condition that results in a loss of mobility and muscle control. A neuropathological hallmark of PD is the presence of aberrant inclusions, known as Lewy pathology, of which α-synuclein (α-Syn) is a major component. The accumulation of α-Syn may be due to an imbalance in the proteostasis system regulating α-Syn. To investigate this hypothesis, we delineated the proteostasis network (PN) of α-Syn in the human substantia nigra at the proteomic and transcriptomic level. We then defined an α-Syn proteostasis activity score (PAS) that quantifiably describes the relative activity of the α-Syn PN in promoting or inhibiting α-Syn aggregation. We report a corresponding PAS signature indicative of disease state, age-of-death in PD patients, and brain regional vulnerability to α-Syn aggregation in PD and healthy brains. After establishing the relevance of our network to PD, we developed a transcriptome-derived network model as an operational digital twin of the α-Syn PN in human substantia nigra cells from single-cell data and used it to prioritize candidate targets for PD. We then further showed the application of the α-Syn PN toward facilitating drug repurposing. Overall, this proof-of-concept study illustrates how our computational framework can identify and prioritize putative therapeutic targets and repurposing candidates for PD, providing testable hypotheses for experimental validation.