TwinF interface inhibitor FP802 prevents retinal ganglion cell loss in a mouse model of amyotrophic lateral sclerosis

IF 6.2 2区 医学 Q1 NEUROSCIENCES Acta Neuropathologica Communications Pub Date : 2024-09-12 DOI:10.1186/s40478-024-01858-0
Yu Meng Wang, Jing Yan, Sarah K. Williams, Richard Fairless, Hilmar Bading
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Abstract

Motor neuron loss is well recognized in amyotrophic lateral sclerosis (ALS), but research on retinal ganglion cells (RGCs) is limited. Ocular symptoms are generally not considered classic ALS symptoms, although RGCs and spinal motor neurons share certain cell pathologies, including hallmark signs of glutamate neurotoxicity, which may be triggered by activation of extrasynaptic NMDA receptors (NMDARs). To explore potential novel strategies to prevent ALS-associated death of RGCs, we utilized inhibition of the TwinF interface, a new pharmacological principle that detoxifies extrasynaptic NMDARs by disrupting the NMDAR/TRPM4 death signaling complex. Using the ALS mouse model SOD1G93A, we found that the small molecule TwinF interface inhibitor FP802 prevents the loss of RGCs, improves pattern electroretinogram (pERG) performance, increases the retinal expression of Bdnf, and restores the retinal expression of the immediate early genes, Inhibin beta A and Npas4. Thus, FP802 not only prevents, as recently described, death of spinal motor neurons in SOD1G93A mice, but it also mitigates ALS-associated retinal damage. TwinF interface inhibitors have great potential for alleviating neuro-ophthalmologic symptoms in ALS patients and offer a promising new avenue for therapeutic intervention.
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双F界面抑制剂FP802可防止肌萎缩性脊髓侧索硬化症小鼠模型中视网膜神经节细胞的丧失
肌萎缩性脊髓侧索硬化症(ALS)的运动神经元缺失是公认的,但对视网膜神经节细胞(RGC)的研究却很有限。眼部症状通常不被认为是典型的渐冻症症状,尽管RGCs和脊髓运动神经元具有某些共同的细胞病理特征,包括谷氨酸神经毒性的标志性症状,这可能是由突触外NMDA受体(NMDARs)激活引发的。为了探索预防与渐冻症相关的 RGCs 死亡的潜在新策略,我们利用了抑制 TwinF 接口的方法,这是一种新的药理学原理,通过破坏 NMDAR/TRPM4 死亡信号复合物来解毒突触外 NMDAR。通过 ALS 小鼠模型 SOD1G93A,我们发现小分子 TwinF 接口抑制剂 FP802 可以防止 RGC 的丧失,改善模式视网膜电图(pERG)表现,增加视网膜中 Bdnf 的表达,并恢复视网膜中即时早期基因 Inhibin beta A 和 Npas4 的表达。因此,FP802 不仅能防止最近描述的 SOD1G93A 小鼠脊髓运动神经元的死亡,还能减轻 ALS 相关的视网膜损伤。双F界面抑制剂在缓解 ALS 患者的神经眼科症状方面具有巨大潜力,为治疗干预提供了一条前景广阔的新途径。
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来源期刊
Acta Neuropathologica Communications
Acta Neuropathologica Communications Medicine-Pathology and Forensic Medicine
CiteScore
11.20
自引率
2.80%
发文量
162
审稿时长
8 weeks
期刊介绍: "Acta Neuropathologica Communications (ANC)" is a peer-reviewed journal that specializes in the rapid publication of research articles focused on the mechanisms underlying neurological diseases. The journal emphasizes the use of molecular, cellular, and morphological techniques applied to experimental or human tissues to investigate the pathogenesis of neurological disorders. ANC is committed to a fast-track publication process, aiming to publish accepted manuscripts within two months of submission. This expedited timeline is designed to ensure that the latest findings in neuroscience and pathology are disseminated quickly to the scientific community, fostering rapid advancements in the field of neurology and neuroscience. The journal's focus on cutting-edge research and its swift publication schedule make it a valuable resource for researchers, clinicians, and other professionals interested in the study and treatment of neurological conditions.
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