Edinburgh Medical School: Biomedical Sciences, University of Edinburgh; Edinburgh, UK; Euan MacDonald Centre for Motor Neuron Disease Research; Edinburgh, UK.
Nuffield Department of Clinical Neurosciences, University of Oxford; Oxford, UK.
EBioMedicine. 2022 Sep;83:104202. doi: 10.1016/j.ebiom.2022.104202. Epub 2022 Aug 11.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with heterogeneous aetiology and a complex genetic background. Effective therapies are therefore likely to act on convergent pathways such as dysregulated energy metabolism, linked to multiple neurodegenerative diseases including ALS.
Activity of the glycolysis enzyme phosphoglycerate kinase 1 (PGK1) was increased genetically or pharmacologically using terazosin in zebrafish, mouse and ESC-derived motor neuron models of ALS. Multiple disease phenotypes were assessed to determine the therapeutic potential of this approach, including axon growth and motor behaviour, survival and cell death following oxidative stress.
We have found that targeting a single bioenergetic protein, PGK1, modulates motor neuron vulnerability in vivo. In zebrafish models of ALS, overexpression of PGK1 rescued motor axon phenotypes and improved motor behaviour. Treatment with terazosin, an FDA-approved compound with a known non-canonical action of increasing PGK1 activity, also improved these phenotypes. Terazosin treatment extended survival, improved motor phenotypes and increased motor neuron number in Thy1-hTDP-43 mice. In ESC-derived motor neurons expressing TDP-43, terazosin protected against oxidative stress-induced cell death and increased basal glycolysis rates, while rescuing stress granule assembly.
Our data demonstrate that terazosin protects motor neurons via multiple pathways, including upregulating glycolysis and rescuing stress granule formation. Repurposing terazosin therefore has the potential to increase the limited therapeutic options across all forms of ALS, irrespective of disease cause.
This work was supported by project grant funding from MND Scotland, the My Name'5 Doddie Foundation, Medical Research Council Doctoral Student Training Fellowship [Ref: BST0010Z] and Academy of Medical Sciences grant [SGL023\1100].
肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，病因多样，遗传背景复杂。因此，有效的治疗方法可能作用于代谢紊乱等汇聚途径，这与包括 ALS 在内的多种神经退行性疾病有关。
通过在斑马鱼、小鼠和 ESC 衍生的 ALS 运动神经元模型中使用特拉唑嗪遗传或药理学增加糖酵解酶磷酸甘油酸激酶 1（PGK1）的活性。评估了多种疾病表型，以确定这种方法的治疗潜力，包括轴突生长和运动行为、氧化应激后的存活和细胞死亡。
我们发现，靶向单个生物能量蛋白 PGK1，可以调节体内运动神经元的易感性。在 ALS 斑马鱼模型中，过表达 PGK1 挽救了运动轴突表型并改善了运动行为。用特拉唑嗪治疗，一种具有增加 PGK1 活性的已知非经典作用的 FDA 批准的化合物，也改善了这些表型。特拉唑嗪治疗延长了 Thy1-hTDP-43 小鼠的存活时间，改善了运动表型并增加了运动神经元数量。在表达 TDP-43 的 ESC 衍生运动神经元中，特拉唑嗪可防止氧化应激诱导的细胞死亡并增加基础糖酵解率，同时挽救应激颗粒的组装。
我们的数据表明，特拉唑嗪通过多种途径保护运动神经元，包括上调糖酵解和挽救应激颗粒形成。因此，重新利用特拉唑嗪有可能增加所有形式 ALS 的有限治疗选择，而与疾病原因无关。
这项工作得到了苏格兰 MND 基金会、My Name'5 Doddie 基金会、医学研究委员会博士学生培训奖学金[Ref：BST0010Z]和医学科学院拨款[ SGL023\1100]的项目资助。
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