Valderhaug Vibeke Devold, Ramstad Ola Huse, van de Wijdeven Rosanne, Heiney Kristine, Nichele Stefano, Sandvig Axel, Sandvig Ioanna
Department of Research and Innovation, Møre and Romsdal Hospital Trust, Ålesund, Norway.
Department of Neuromedicine and Movement Science, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
Front Cell Neurosci. 2024 Apr 5;18:1366098. doi: 10.3389/fncel.2024.1366098. eCollection 2024.
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been widely linked to Parkinson's disease, where the G2019S variant has been shown to contribute uniquely to both familial and sporadic forms of the disease. LRRK2-related mutations have been extensively studied, yet the wide variety of cellular and network events related to these mutations remain poorly understood. The advancement and availability of tools for neural engineering now enable modeling of selected pathological aspects of neurodegenerative disease in human neural networks . Our study revealed distinct pathology associated dynamics in engineered human cortical neural networks carrying the LRRK2 G2019S mutation compared to healthy isogenic control neural networks. The neurons carrying the LRRK2 G2019S mutation self-organized into networks with aberrant morphology and mitochondrial dynamics, affecting emerging structure-function relationships both at the micro-and mesoscale. Taken together, the findings of our study points toward an overall heightened metabolic demand in networks carrying the LRRK2 G2019S mutation, as well as a resilience to change in response to perturbation, compared to healthy isogenic controls.
富含亮氨酸重复激酶2（LRRK2）基因的突变与帕金森病广泛相关，其中G2019S变体已被证明对该疾病的家族性和散发性形式均有独特影响。与LRRK2相关的突变已得到广泛研究，但与这些突变相关的各种细胞和网络事件仍知之甚少。神经工程工具的进步和可用性现在使得在人类神经网络中对神经退行性疾病的选定病理方面进行建模成为可能。我们的研究揭示，与健康的同基因对照神经网络相比，携带LRRK2 G2019S突变的工程化人类皮层神经网络中存在独特的病理相关动力学。携带LRRK2 G2019S突变的神经元自组织成形态和线粒体动力学异常的网络，在微观和中观尺度上影响新出现的结构-功能关系。综上所述，我们的研究结果表明，与健康的同基因对照相比，携带LRRK2 G2019S突变的网络总体代谢需求增加，并且对扰动响应的变化具有恢复力。
