Although the molecular mechanisms underlying amyotrophic lateral sclerosis (ALS) are not yet fully understood, recent studies have described alterations in tau protein in both sporadic and familial ALS. However, it is unclear whether alterations in tau contribute to ALS pathogenesis. Here, we leveraged the ALS Knowledge Portal and Project MinE data sets and identified specific genetic variants clustering within the microtubule-binding domain of MAPT, which were unique to ALS cases. Furthermore, our analysis in a large post-mortem cohort of ALS and control motor cortex demonstrates that although there was no significant difference in the presence of phosphorylated tau (pTau) neuropil threads and neurofibrillary tangles between the two groups, pTau-S396 and pTau-S404 mis-localized to the nucleus and synapses in ALS. This was specific to the C-terminus phosphorylation sites as there was a significant decrease in pTau-T181 in ALS synaptoneurosomes compared to controls. Lastly, while there was no change in total tau or pTau-T181 in ALS CSF, there was a decrease in pTau-T181:tau ratio in ALS CSF, as previously reported. Importantly, CSF tau levels were increased in ALS patients diagnosed with bulbar onset ALS, while pTau-T181:tau ratio was decreased in ALS patients diagnosed with both bulbar and limb onset. Additionally, there was an inverse correlation between tau levels in the CSF and the revised ALS functional rating scale (ALSFRS-R) as well as a correlation between pTau-T181:tau ratio and ALSFRS-R. While there were no longitudinal alterations in tau, pTau-T181 and pTau-T181:tau ratio, there was an increase in the rate of ALSFRS-R decline per month associated with increases in tau levels. This decline was also inversely correlated with increases in pTau-T181 in relation to tau levels. Taken together, our findings demonstrate that, like Alzheimer's disease, hyperphosphorylated tau is mis-localized in ALS and that decreases in CSF pTau-T181 may serve as a biomarker in ALS.

中文翻译：

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肌萎缩侧索硬化病死运动皮层和脑脊液中磷酸化tau蛋白的深入分析

尽管尚未完全了解肌萎缩性侧索硬化症（ALS）的分子机制，但最近的研究已经描述了散发性和家族性ALS中tau蛋白的改变。然而，目前尚不清楚tau蛋白的改变是否与ALS发病有关。在这里，我们利用了ALS知识门户网站和Project MinE数据集，并确定了MAPT的微管结合域内聚集的特定遗传变异，这是ALS病例所独有的。此外，我们在大型ALS和对照运动皮层的验尸队列中的分析表明，尽管两组中pTau-S396和pTau--的磷酸化tau（pTau）神经纤维和神经原纤维缠结的存在没有显着差异。 S404错误定位到ALS的核和突触。这对C末端磷酸化位点是特异的，因为与对照相比，ALS突触神经小体中pTau-T181显着降低。最后，虽然ALS CSF的总tau或pTau-T181没有变化，但ALS CSF的pTau-T181：tau比值有所降低，如先前报道。重要的是，在诊断患有延髓发作性ALS的ALS患者中，脑脊液tau水平升高，而在同时患有延髓性和四肢发作的ALS患者中，pTau-T181：tau比降低。此外，CSF中的tau水平与修订的ALS功能评定量表（ALSFRS-R）之间存在负相关，而pTau-T181：tau比与ALSFRS-R之间也存在负相关。尽管tau，pTau-T181和pTau-T181：tau之比没有纵向变化，与tau水平升高相关的ALSFRS-R下降率每月都有所增加。该下降也与pTau-T181相对于tau水平的升高呈负相关。综上所述，我们的发现表明，与阿尔茨海默氏病一样，磷酸化的tau在ALS中定位错误，而CSF pTau-T181的降低可能是ALS的生物标记。