2. Academic Validation
  3. Network analysis of α-synuclein pathology progression reveals p21-activated kinases as regulators of vulnerability

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

  • bioRxiv. 2024 Oct 22:2024.10.22.619411. doi: 10.1101/2024.10.22.619411.
Naman Vatsa 1 2,  Julia K Brynildsen 2 3,  Thomas M Goralski 1 2,  Kevin Kurgat 1 2,  Lindsay Meyerdirk 1 2,  Libby Breton 1 2,  Daniella DeWeerd 1 2,  Laura Brasseur 1 2,  Lisa Turner 4,  Katelyn Becker 4,  Kristin L Gallik 4,  Dani S Bassett 2 3 5 6 7 8 9 10,  Michael X Henderson 1 2 11
Affiliations

Affiliations

  • 1 Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA.
  • 2 Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
  • 3 Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
  • 4 Van Andel Institute, Grand Rapids, MI, USA.
  • 5 Department of Electrical & Systems Engineering, University of Pennsylvania, Philadelphia, PA, USA.
  • 6 Department of Physics & Astronomy, University of Pennsylvania, Philadelphia, PA, USA.
  • 7 Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA.
  • 8 Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
  • 9 Santa Fe Institute, Santa Fe, NM, USA.
  • 10 Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
  • 11 Lead Contact.
PMID: 39484617 DOI: 10.1101/2024.10.22.619411
Abstract

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.

Keywords

Network vulnerability; PAK5; PAK6; Snca; computational modeling; mitochondria; p21-activated kinase.

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