用新的生物学见解破解 ALS 生存差异之谜

Patients with ALS, or Lou Gehrig's disease, live an average of only three years after symptoms begin, though some can survive closer to 10 years. What drives these differences in survival has remained a mystery.

ALS（即 Lou Gehrig 病）患者在症状开始后平均仅能存活三年，不过有些患者可存活接近 10 年。是什么驱动了这些生存差异，一直是一个谜。

A new Northwestern Medicine study provides new insight, identifying evidence that ALS unfolds through a domino-like sequence of events that begins with an early breakdown inside motor neurons and is followed by a damaging inflammatory response. The findings help explain why the disease worsens over time, why some patients progress faster than others and how future treatments could be more personalized.

一项新的 Northwestern Medicine 研究提供了新的见解，发现证据表明 ALS 是通过一连串类似多米诺骨牌的事件展开的：最初是运动神经元内部早期出现崩解，随后发生有害的炎症反应。这些发现有助于解释为什么疾病会随着时间推移而恶化，为什么有些患者进展比其他患者更快，以及未来治疗如何能够更加个体化。

The study will be published on May 14th, 2026, in Nature Neuroscience.

该研究将于 2026 年 5 月 14 日发表在《Nature Neuroscience》上。

"This study reveals that ALS is not a single event but a domino-like cascade that begins inside motor neurons with TDP-43 pathology and is then amplified by a damaging immune response in the bloodstream and spinal cord," said co-corresponding author David Gate, director of the Abrams Research Center on Neurogenomics at Northwestern University Feinberg School of Medicine.

“这项研究揭示，ALS 并不是一个单一事件，而是一种类似多米诺骨牌的级联过程：它始于运动神经元内部的 TDP-43 病理改变，随后被血液和脊髓中的有害免疫反应放大，”共同通讯作者 David Gate 说，他是 Northwestern University Feinberg School of Medicine 的 Abrams Research Center on Neurogenomics 主任。

The study found immune cells converge at sites of motor neuron loss and TDP-43 pathology - a hallmark of ALS - with distinct inflammatory patterns depending on the type of ALS (genetic or non-genetic, the most common form) and how quickly the disease progresses.

研究发现，免疫细胞会聚集到运动神经元丧失和 TDP-43 病理改变的部位——这是 ALS 的一个标志——并且根据 ALS 类型（遗传性或非遗传性，后者是最常见形式）以及疾病进展速度，呈现出不同的炎症模式。

"The intensity of spinal cord inflammation doesn't determine when someone develops ALS - it determines how fast the disease progresses and how long they survive," said co-corresponding author Evangelos Kiskinis, associate professor of neurology and neuroscience at Feinberg. "If we can target these immune signatures therapeutically, we can slow down the rate of disease progression."

“脊髓炎症的强度并不决定一个人何时发生 ALS——它决定疾病进展有多快以及患者能存活多久，”共同通讯作者 Evangelos Kiskinis 说，他是 Feinberg 神经病学和神经科学副教授。“如果我们能够以治疗方式靶向这些免疫特征，就能减缓疾病进展速度。”

Using cutting-edge techniques, the scientists analyzed blood and spinal cord samples from almost 300 patients - living and deceased - with both non-genetic and genetic (caused by changes in the C9orf72 gene) forms of ALS, as well as controls.

科学家们使用前沿技术，分析了近 300 名患者的血液和脊髓样本——包括在世和已故患者——这些患者患有非遗传性和遗传性（由 C9orf72 基因改变引起）ALS，同时还分析了对照样本。

"We found the immune cells we detected in the blood of people living with ALS were inflamed, and we found the genes that mediate their inflammatory response in the spinal cord at the site of motor neurons," Gate said. "These inflamed immune cells were associated with ALS pathology, giving some credence to our theory that the immune system is detrimental. It's responding to pathology, and it's causing the disease to be worse."

“我们发现，在 ALS 患者血液中检测到的免疫细胞处于炎症状态，并且在脊髓中运动神经元所在部位发现了介导其炎症反应的基因，”Gate 说。“这些炎症性免疫细胞与 ALS 病理改变相关，这在一定程度上支持了我们的理论，即免疫系统是有害的。它在对病理改变作出反应，并且正在使疾病变得更严重。”

The findings suggest if treatments can target these immune signatures, they can slow down the rate of disease progression, and that future therapeutics may need to be tailored to specific ALS subtypes and disease stages to be most effective, the authors said.

作者表示，这些发现提示，如果治疗能够靶向这些免疫特征，就能减缓疾病进展速度；未来疗法可能需要针对特定 ALS 亚型和疾病阶段进行定制，才能发挥最佳效果。

"For ALS, this work is highly novel," said Gate, also an assistant professor of neurology at Feinberg. "This is the first in-depth molecular assessment of how the immune system behaves across different forms of ALS, using technologies that allow us to pinpoint which immune genes are active in patient tissues, and where."

“对于 ALS 来说，这项工作具有很高的新颖性，”Gate 说，他也是 Feinberg 神经病学助理教授。“这是首次利用能够确定患者组织中哪些免疫基因处于活跃状态以及其所在位置的技术，对免疫系统在不同形式 ALS 中的行为进行深入分子评估。”

The scientists used single-cell RNA sequencing technology to analyze blood samples from 40 living ALS patients and used spatial transcriptomics, a technique that allows them to pinpoint the specific spatial location of gene activity inside a tissue sample, to analyze spinal cord tissue from 18 deceased participants. They compared patients with non-genetic ALS to those with the genetic form, which allowed the scientists to see how immune activity differs across ALS types and disease stages. To further analyze inflammatory responses within the central nervous system of ALS patients, the scientists examined RNA from postmortem samples of 237 ALS patients.

科学家们使用单细胞 RNA 测序技术分析了 40 名在世 ALS 患者的血液样本，并使用空间转录组学分析了 18 名已故参与者的脊髓组织；空间转录组学是一种能够精确定位组织样本内基因活动具体空间位置的技术。他们将非遗传性 ALS 患者与遗传性 ALS 患者进行比较，使科学家能够看到不同 ALS 类型和疾病阶段之间免疫活动如何不同。为进一步分析 ALS 患者中枢神经系统内的炎症反应，科学家们检查了 237 名 ALS 患者死后样本中的 RNA。

Patients whose disease advanced quickly showed heightened activity in certain immune genes, while those with the genetic form had a different array of altered immune genes. In the spinal cord, these activated immune cells gathered directly at the locations of motor neuron loss and near the toxic protein buildups characteristic of ALS.

疾病进展较快的患者在某些免疫基因上表现出增强的活动，而遗传性 ALS 患者则有另一组发生改变的免疫基因。在脊髓中，这些被激活的免疫细胞直接聚集在运动神经元丧失的位置，以及 ALS 特征性的毒性蛋白堆积附近。

"We saw that people with worse clinical ALS had more expression of complement genes, which are proteins that become activated as the body's first-line immune defense against a pathogen or damage to the body," Gate said.

“我们看到，临床 ALS 更严重的人补体基因表达更多；补体基因编码的蛋白会作为人体抵御病原体或身体损伤的第一线免疫防御而被激活，”Gate 说。

Having identified a direct link between the immune system and ALS, Gate said the next step for his lab is to expand the research to include more patients and to more closely study the motor circuit, which is the neural command system that carries signals from the brain, through the spinal cord, to the muscles.

Gate 说，在确定免疫系统与 ALS 之间存在直接联系后，他的实验室下一步将扩大研究，纳入更多患者，并更深入地研究运动环路；运动环路是将信号从大脑经脊髓传递到肌肉的神经指挥系统。

"Our next step is to map exactly how this immune reaction spreads throughout the entire motor circuit: from the brain, down through the spinal cord and out to the muscles," Gate said. "By profiling the motor circuit in depth, we'll get a much clearer picture of where and when inflammation drives faster progression, which should help us develop immune-targeted therapies that slow the disease and extend survival across ALS subtypes," Gate said.

“我们的下一步是精确绘制这种免疫反应如何在整个运动环路中扩散：从大脑出发，沿脊髓向下，再到肌肉，”Gate 说。“通过深入描绘运动环路，我们将更清楚地了解炎症在何处以及何时驱动更快进展，这应有助于我们开发靶向免疫的疗法，以减缓疾病并延长不同 ALS 亚型患者的生存期，”Gate 说。

The next step for Kiskinis' lab will be testing if there is a causal relationship between TDP-43 dysfunction and inflammation, which he suspects.

Kiskinis 实验室的下一步将是检验 TDP-43 功能障碍与炎症之间是否存在因果关系，他怀疑确实存在这种关系。

"We're trying to really define what is the mechanism that links TDP-43 dysfunction in nerve cells with inflammatory reactions," Kiskinis said.

“我们正试图真正明确，将神经细胞中的 TDP-43 功能障碍与炎症反应联系起来的机制是什么，”Kiskinis 说。