Vatsa Naman, Brynildsen Julia K, Goralski Thomas M, Kurgat Kevin, Meyerdirk Lindsay, Breton Libby, DeWeerd Daniella, Brasseur Laura, Turner Lisa, Becker Katelyn, Gallik Kristin L, Bassett Dani S, Henderson Michael X
Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA.
Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
bioRxiv. 2024 Oct 22:2024.10.22.619411. doi: 10.1101/2024.10.22.619411.
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.
α-突触核蛋白的错误折叠和渐进性积累驱动了帕金森病的致病过程。为了解细胞和神经网络对α-突触核蛋白病理的易损性，我们开发了一个框架来量化网络层面的易损性，并在细胞水平上确定新的治疗靶点。在9个月的时间里对小鼠全脑α-突触核蛋白病理进行了映射。将实验病理数据与基于解剖连接的病理进展扩散模型的理论病理估计值进行了比较。模型中无法解释的差异使我们能够得出区域易损性，并将其与区域基因表达进行比较。我们确定了与区域易损性相关的基因表达模式，包括在易损区域富集的12种激酶。其中，II型PAKs的一种抑制剂即使在延迟化合物治疗后也能保护神经元免于死亡和α-突触核蛋白病理。这项研究为从基于网络的研究中推导细胞易损性提供了一个框架，并确定了一条有前景的帕金森病治疗途径。
