Pilotto Federica, Smeele Paulien Hermine, Scheidegger Olivier, Diab Rim, Schobesberger Martina, Sierra-Delgado Julieth Andrea, Saxena Smita
Institut Neuromyogène, Pathophysiology and Genetics of the Neuron and Muscle, Inserm U1315, CNRS, Université Claude Bernard Lyon I, UMR 5261, 69008, Lyon, France.
Department of Neurology, Inselspital University Hospital, Bern, Switzerland.
Acta Neuropathol Commun. 2025 Feb 1;13(1):21. doi: 10.1186/s40478-025-01927-y.
Repeat expansions in the C9ORF72 gene are a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Considerable progress has been made in identifying C9ORF72-mediated disease and resolving its underlying etiopathogenesis. The contributions of intrinsic mitochondrial deficits as well as chronic endoplasmic reticulum stress to the development of the C9ORF72-linked pathology are well established. Nevertheless, to date, no cure or effective therapy is available, and thus attempts to find a potential drug target, have received increasing attention. Here, we investigated the mode of action and therapeutic effect of a naturally occurring dietary flavanol, kaempferol in preclinical rodent and human models of C9ORF72-ALS. Notably, kaempferol treatment of C9ORF72-ALS human patient-derived motor neurons/neurons, resolved mitochondrial deficits, promoted resiliency against severe ER stress, and conferred neuroprotection. Treatment of symptomatic C9ORF72 mice with kaempferol, normalized mitochondrial calcium uptake, restored mitochondria function, and diminished ER stress. Importantly, in vivo, chronic kaempferol administration ameliorated pathological motor dysfunction and inhibited motor neuron degeneration, highlighting the translational potential of kaempferol. Lastly, in silico modelling identified a novel kaempferol target and mechanistically the neuroprotective mechanism of kaempferol is through the iP3R-VDAC1 pathway via the modulation of GRP75 expression. Thus, kaempferol holds great promise for treating neurodegenerative diseases where both mitochondrial and ER dysfunction are causally linked to the pathophysiology.
C9ORF72基因中的重复扩增是肌萎缩侧索硬化症（ALS）和额颞叶痴呆的常见病因。在识别C9ORF72介导的疾病并解析其潜在的病因发病机制方面已经取得了相当大的进展。内在线粒体缺陷以及慢性内质网应激对C9ORF72相关病理发展的作用已得到充分证实。然而，迄今为止，尚无治愈方法或有效疗法，因此寻找潜在药物靶点的尝试受到了越来越多的关注。在这里，我们研究了天然存在的膳食黄烷醇山奈酚在C9ORF72-ALS临床前啮齿动物模型和人类模型中的作用模式和治疗效果。值得注意的是，用山奈酚处理源自C9ORF72-ALS人类患者的运动神经元/神经元，可解决线粒体缺陷，增强对严重内质网应激的耐受性，并赋予神经保护作用。用山奈酚治疗有症状的C9ORF72小鼠，可使线粒体钙摄取正常化，恢复线粒体功能，并减轻内质网应激。重要的是，在体内，长期给予山奈酚可改善病理性运动功能障碍并抑制运动神经元变性，突出了山奈酚的转化潜力。最后，计算机模拟确定了一个新的山奈酚靶点，从机制上讲，山奈酚的神经保护机制是通过调节GRP75表达经由IP3R-VDAC1途径实现的。因此，山奈酚在治疗线粒体和内质网功能障碍均与病理生理学有因果关系的神经退行性疾病方面具有巨大潜力。
