新策略可阻止驱动 ALS 的有毒蛋白团块：研究

Targeted treatment preserves normal function, extends survival in animal models

靶向治疗保留正常功能并延长动物模型的生存期

Targeting a specific part of the TDP-43 protein can prevent toxic protein clumping that drives amyotrophic lateral sclerosis (ALS) without disrupting the protein’s normal function, a new study shows.

一项新研究显示，针对 TDP-43 蛋白的特定部分，可以阻止驱动肌萎缩侧索硬化症（ALS）的有毒蛋白聚集，同时不会破坏该蛋白的正常功能。

“Current [U.S.-approved] treatments for ALS provide only modest benefits. There is an urgent need for a real breakthrough,” Xinglong Wang, PhD, the study’s senior author and a professor at the University of Arizona’s R. Ken Coit College of Pharmacy, said in a university news story . “We asked a simple question that had never been tested: Is there one specific part of TDP-43 that’s causing the harm, something a drug could switch off without disturbing the rest?”

“目前[获美国批准的] ALS 治疗只能带来有限的益处。我们迫切需要真正的突破，”该研究的资深作者、亚利桑那大学 R. Ken Coit 药学院教授 Xinglong Wang 博士在一篇校方新闻报道中说。“我们提出了一个此前从未被检验过的简单问题：TDP-43 是否存在某个特定部分会造成伤害，可以通过药物将其关闭，同时不干扰其余部分？”

The researchers have already identified a small molecule that is able to target this specific part of the TDP-43 protein, and they showed that this molecule extended survival and decreased nerve damage in a mouse model of ALS.

研究人员已经确定了一种能够靶向 TDP-43 蛋白这一特定部分的小分子，并证明这种分子可在 ALS 小鼠模型中延长生存期、减少神经损伤。

“These findings expand our understanding of TDP-43 neurotoxicity and provide a strong foundation for the development of therapeutic strategies targeting TDP-43-associated neurodegeneration,” researchers wrote.

研究人员写道：“这些发现拓展了我们对 TDP-43 神经毒性的理解，并为开发针对 TDP-43 相关神经退行性变的治疗策略奠定了坚实基础。”

The study, “ Therapeutic targeting of the conserved region within the low-complexity domain of TDP-43 is neuroprotective and extends survival in amyotrophic lateral sclerosis mice ,” was published in Nature Aging .

该研究题为“ Therapeutic targeting of the conserved region within the low-complexity domain of TDP-43 is neuroprotective and extends survival in amyotrophic lateral sclerosis mice ”，发表于 Nature Aging。

ALS is marked by the death of motor neurons, the nerve cells that control movement. The causes of ALS are not fully understood, but a molecular hallmark of the disease is dysregulation of the TDP-43 protein.

ALS 的特征是运动神经元死亡，这些神经细胞负责控制运动。ALS 的病因尚未完全明确，但该疾病的一个分子标志是 TDP-43 蛋白失调。

This protein is normally present in nerve cells and helps regulate gene activity, but in ALS, TDP-43 forms toxic clumps that damage nerve cells and contribute to disease progression. A minority of ALS patients have mutations in TARDBP , the gene that encodes TDP-43, but this protein also forms toxic clumps in ALS patients who don’t have such mutations.

这种蛋白通常存在于神经细胞中，有助于调节基因活性；但在 ALS 中，TDP-43 会形成有毒团块，损伤神经细胞并促成疾病进展。少数 ALS 患者的 TARDBP（编码 TDP-43 的基因）发生突变，但没有这类突变的 ALS 患者体内也会形成有毒的 TDP-43 蛋白团块。

Preventing TDP-43 from forming toxic clumps is widely seen as a promising strategy for developing new ALS treatments . But it’s been difficult for scientists to find a way to prevent these clumps without also disrupting the protein’s normal functions.

阻止 TDP-43 形成有毒团块，被广泛视为开发新型 ALS 治疗方法的一项有前景策略。但科学家一直难以找到一种方法，在阻止这些团块形成的同时不破坏该蛋白的正常功能。

In this study, Wang and colleagues looked in detail at the structure of the TDP-43 protein, hoping to find specific regions that could be targeted to prevent clumping without interfering with the protein’s function.

在这项研究中，Wang 及其同事详细研究了 TDP-43 蛋白的结构，希望找到可以靶向的特定区域，在不干扰蛋白功能的情况下阻止其聚集。

The team zeroed in on a specific part of the TDP-43 protein that is critical for regulating the protein’s functional assembly and is evolutionarily conserved across species. A lot of ALS-associated TARDBP gene mutations specifically affect this conserved region (CR) of the TDP-43 protein.

研究团队聚焦于 TDP-43 蛋白的一个特定部分，该部分对于调节蛋白的功能性组装至关重要，并且在不同物种间进化上高度保守。许多与 ALS 相关的 TARDBP 基因突变，正是影响了 TDP-43 蛋白的这一保守区域（CR）。

The researchers found that increasing the production of the full TDP-43 protein in lab-grown mouse nerve cells triggered protein clumping and nerve damage akin to what’s seen in ALS. But when the researchers promoted the production of a version of the TDP-43 protein where the CR was deleted, the protein didn’t clump or cause damage.

研究人员发现，在实验室培养的小鼠神经细胞中提高完整 TDP-43 蛋白的生成，会引发类似 ALS 中所见的蛋白聚集和神经损伤。但当研究人员促进生成缺失 CR 的 TDP-43 蛋白变体时，该蛋白既不会聚集，也不会造成损伤。

“These results collectively suggest that CR is critical in mediating neuronal toxicity induced by [high levels of] TDP-43,” the researchers wrote.

研究人员写道：“这些结果共同表明，CR 在介导[高水平的] TDP-43 诱导的神经元毒性方面至关重要。”

In a wide range of further experiments, the team showed that deleting the CR from TDP-43 doesn’t disturb the protein’s natural function. According to Wang, most of this decade-long study was dedicated to tests to ensure that deleting the CR wouldn’t cause unexpected problems.

在一系列广泛的后续实验中，研究团队证明，从 TDP-43 中删除 CR 不会干扰该蛋白的自然功能。Wang 表示，这项历时十年的研究大部分时间都用于开展测试，以确保删除 CR 不会引发意外问题。

“By targeting a domain essential for neurotoxicity without disrupting key [protein] functions, we show that TDP-43-associated neurodegeneration may be effectively suppressed,” the scientists wrote.

科学家们写道：“通过靶向对神经毒性至关重要的结构域，同时不破坏关键的[蛋白]功能，我们表明 TDP-43 相关神经退行性变可能得到有效抑制。”

After confirming that such functions wouldn’t be disrupted, the researchers set out to find small molecules that could target the CR region in TDP-43. They identified one such small molecule, called XL20, that is able to cross into the brain and specifically target the CR.

在确认这些功能不会受到干扰后，研究人员开始寻找能够靶向 TDP-43 中 CR 区域的小分子。他们确定了一种名为 XL20 的小分子，该分子能够进入大脑并特异性靶向 CR。

Perhaps one of the most promising aspects of this study is the identification of a potent small molecule capable of binding TDP-43 to suppress its neurotoxicity without impacting [the protein’s main localization and] function.

这项研究最有前景的方面之一，或许是发现了一种能够与 TDP-43 结合的强效小分子，在不影响[该蛋白的主要定位和]功能的情况下抑制其神经毒性。

In lab-grown human motor neurons, treatment with XL20 reduced nerve damage driven by TDP-43 clumping. And in mice with a TARDBP gene mutation (widely used as a model of ALS), XL20 treatment led to improved motor function and modest extensions in lifespan. The researchers also confirmed that XL20 treatment didn’t disrupt TDP-43’s normal activities.

在实验室培养的人类运动神经元中，XL20 治疗减少了由 TDP-43 聚集引起的神经损伤。而在携带 TARDBP 基因突变的小鼠中（这种小鼠被广泛用作 ALS 模型），XL20 治疗改善了运动功能，并使寿命得到有限延长。研究人员还确认，XL20 治疗没有干扰 TDP-43 的正常活动。

“Perhaps one of the most promising aspects of this study is the identification of a potent small molecule capable of binding TDP-43 to suppress its neurotoxicity without impacting [the protein’s main localization and] function,” the researchers wrote.

研究人员写道：“这项研究最有前景的方面之一，或许是发现了一种能够与 TDP-43 结合的强效小分子，在不影响[该蛋白的主要定位和]功能的情况下抑制其神经毒性。”

The team said these findings position XL20 as a promising potential treatment for ALS. And because TDP-43 has also been implicated in other neurological disorders, the findings may have implications for other diseases.

研究团队表示，这些发现使 XL20 成为一种有潜力的 ALS 治疗方法。由于 TDP-43 也被认为与其他神经系统疾病有关，这些发现可能对其他疾病产生影响。

“If future studies show this approach works in those diseases as well, it could eventually benefit a much larger patient population,” Wang said.

Wang 说：“如果未来研究显示这一方法同样适用于那些疾病，那么最终可能使数量更多的患者群体受益。”