Li Yuanxi, Torok Justin, Zhang Shujing, Ding Jessica, Wang Ning, Lau Courtney, Kulkarni Shruti, Anand Chaitali, Tran Julie, Cheng Michael, Lo Claire, Lu Binbin, Sun Yanzi, Damoiseaux Robert, Yang Xia, Raj Ashish, Peng Chao
Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Institute for Cognitive Neurodynamics, East China University of Science and Technology, Shanghai, 200237, China.
Adv Sci (Weinh). 2025 Jul;12(25):e2413052. doi: 10.1002/advs.202413052. Epub 2025 May 28.
Previous studies have suggested that pathological α-synuclein (α-Syn) mainly transmits along the neuronal network, but several key questions remain unanswered: 1) How many and which connections in the connectome are necessary for predicting the progression of pathological α-Syn? 2) How to identify risk genes that affect pathology spreading functioning at presynaptic or postsynaptic regions, and are these genes enriched in different cell types? Here, these questions are addressed with novel mathematical models. Strikingly, the spreading of pathological α-Syn is predominantly determined by the key subnetworks composed of only 2% of the strongest connections in the connectome. Genes associated with the selective vulnerability of brain regions to pathological α-Syn transmission are further analyzed to distinguish those functioning at presynaptic versus postsynaptic regions. Those risk genes are significantly enriched in microglial cells of presynaptic regions and neurons of postsynaptic regions. Gene regulatory network analyses are then conducted to identify "key drivers" of genes responsible for selective vulnerability and overlapping with Parkinson's disease risk genes. By identifying and discriminating between key gene mediators of transmission operating at presynaptic and postsynaptic regions, this study has demonstrated for the first time that these are functionally distinct processes.
先前的研究表明，病理性α-突触核蛋白（α-Syn）主要沿神经网络传播，但仍有几个关键问题未得到解答：1）连接组中哪些连接以及有多少连接对于预测病理性α-Syn的进展是必要的？2）如何识别影响病理传播的风险基因，这些基因在突触前或突触后区域发挥作用，并且这些基因在不同细胞类型中是否富集？在这里，这些问题通过新颖的数学模型得到了解答。令人惊讶的是，病理性α-Syn的传播主要由仅占连接组中2%最强连接组成的关键子网所决定。进一步分析与脑区对病理性α-Syn传播的选择性易损性相关的基因，以区分那些在突触前与突触后区域发挥作用的基因。这些风险基因在突触前区域的小胶质细胞和突触后区域的神经元中显著富集。然后进行基因调控网络分析，以识别负责选择性易损性且与帕金森病风险基因重叠的基因的“关键驱动因素”。通过识别和区分在突触前和突触后区域起作用的关键基因介导的传播，本研究首次证明这些是功能不同的过程。
