School of Infection and Immunity, University of Glasgow, Glasgow, UK.
Institute for Neuropathology, University Medical Center Göttingen, Göttingen, Germany.
Neuropathol Appl Neurobiol. 2023 Oct;49(5):e12935. doi: 10.1111/nan.12935.
Fibroblast growth factor (FGF) signalling is dysregulated in multiple sclerosis (MS) and other neurological and psychiatric conditions, but there is little or no consensus as to how individual FGF family members contribute to disease pathogenesis. Lesion development in MS is associated with increased expression of FGF1, FGF2 and FGF9, all of which modulate remyelination in a variety of experimental settings. However, FGF9 is also selectively upregulated in major depressive disorder (MDD), prompting us to speculate it may also have a direct effect on neuronal function and survival.
Transcriptional profiling of myelinating cultures treated with FGF1, FGF2 or FGF9 was performed, and the effects of FGF9 on cortical neurons investigated using a combination of transcriptional, electrophysiological and immunofluorescence microscopic techniques. The in vivo effects of FGF9 were explored by stereotactic injection of adeno-associated viral (AAV) vectors encoding either FGF9 or EGFP into the rat motor cortex.
Transcriptional profiling of myelinating cultures after FGF9 treatment revealed a distinct neuronal response with a pronounced downregulation of gene networks associated with axonal transport and synaptic function. In cortical neuronal cultures, FGF9 also rapidly downregulated expression of genes associated with synaptic function. This was associated with a complete block in the development of photo-inducible spiking activity, as demonstrated using multi-electrode recordings of channel rhodopsin-transfected rat cortical neurons in vitro and, ultimately, neuronal cell death. Overexpression of FGF9 in vivo resulted in rapid loss of neurons and subsequent development of chronic grey matter lesions with neuroaxonal reduction and ensuing myelin loss.
These observations identify overexpression of FGF9 as a mechanism by which neuroaxonal pathology could develop independently of immune-mediated demyelination in MS. We suggest targeting neuronal FGF9-dependent pathways may provide a novel strategy to slow if not halt neuroaxonal atrophy and loss in MS, MDD and potentially other neurodegenerative diseases.
成纤维细胞生长因子（FGF）信号在多发性硬化症（MS）和其他神经和精神疾病中失调，但对于单个 FGF 家族成员如何促进疾病发病机制，目前仍存在较少或没有共识。MS 中的病变发展与 FGF1、FGF2 和 FGF9 的表达增加有关，所有这些因子在各种实验环境中都调节着髓鞘的再形成。然而，FGF9 在重度抑郁症（MDD）中也被选择性地上调，这促使我们推测它也可能对神经元功能和存活有直接影响。
对用 FGF1、FGF2 或 FGF9 处理的髓鞘形成培养物进行转录谱分析，并使用转录组学、电生理学和免疫荧光显微镜技术组合研究 FGF9 对皮质神经元的影响。通过立体定向注射编码 FGF9 或 EGFP 的腺相关病毒（AAV）载体到大鼠运动皮层，探索 FGF9 的体内作用。
FGF9 处理后的髓鞘形成培养物的转录谱分析显示出明显的神经元反应，与轴突运输和突触功能相关的基因网络显著下调。在皮质神经元培养物中，FGF9 也迅速下调了与突触功能相关的基因表达。这与使用多电极记录体外转染通道视紫红质的大鼠皮质神经元的光诱导放电活性的完全阻断有关，最终导致神经元细胞死亡。体内过表达 FGF9 导致神经元迅速丧失，随后发展为慢性灰质病变，伴有神经轴突减少和随后的髓鞘丢失。
这些观察结果表明，FGF9 的过表达是神经轴突病理学在 MS 中独立于免疫介导的脱髓鞘而发展的一种机制。我们建议靶向神经元 FGF9 依赖性途径可能提供一种新的策略，以减缓甚至阻止 MS、MDD 以及潜在的其他神经退行性疾病中的神经轴突萎缩和丧失。
