Network analysis of α-synuclein pathology progression reveals p21-activated kinases as regulators of vulnerability

α-Synuclein misfolding and progressive accumulation drives a pathogenic process in Parkinson’s disease. To understand cellular and network vulnerability to α-synuclein pathology, we developed a framework to quantify network-level vulnerability and identify new therapeutic targets at the cellular level. Full brain α-synuclein pathology was mapped in mice over 9 months. Empirical pathology data was compared to theoretical pathology estimates from a diffusion model of pathology progression along anatomical connections. Unexplained variance in the model enabled us to derive regional vulnerability that we compared to regional gene expression. We identified gene expression patterns that relate to regional vulnerability, including 12 kinases that were enriched in vulnerable regions. Among these, an inhibitor of group II PAKs demonstrated protection from neuron death and α-synuclein pathology, even after delayed compound treatment. This study provides a framework for the derivation of cellular vulnerability from network-based studies and identifies a promising therapeutic pathway for Parkinson’s disease.

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HIGHLIGHTS

• Longitudinal α-synuclein pathology assessment in 1046 brain regions over 9 months

• Linear diffusion modeling derivation of network vulnerability to α-synuclein pathology

• PANGEA: assessment of over 19,000 genes in 302 brain regions

• Group II PAK inhibitor prevents α-synuclein pathology and neuron death