Autism manifests in myriad forms. Symptoms and severity vary from person to person, but all autism spectrum disorders share three core symptoms: impaired social interactions, communication deficits, and excessive repetitive behaviors.
No existing medications can adequately treat the core symptoms, and new treatments are urgently needed.
Now, researchers at the Gladstone Institutes report in Neuron that reducing levels of a protein called tau prevents the core symptoms from arising in mouse models simulating different forms of autism spectrum disorders. Tau reduction in these mice also prevented seizures, which occur in 30 percent of people with autism.
"Our findings suggest that tau reduction holds promise as a potential treatment for some forms of autism," said Lennart Mucke, MD, the founding director of the Gladstone Institute of Neurological Disease and senior author of the new paper.
Tau has never before been linked to autism, but it is known for its role in Alzheimer's disease and other neurodegenerative conditions.
"We've uncovered an unexpected new connection between degenerative diseases of aging and developmental disorders of childhood," said Mucke, who is also a professor of neurology and neuroscience at the University of California, San Francisco.
Making the Leap from Alzheimer's to Autism
These surprising findings stem from an investigation of links between Alzheimer's disease and epilepsy. Originally, Mucke and colleagues showed that tau reduction prevents epileptic activity and cognitive deficits in mouse models of Alzheimer's disease and of Dravet syndrome, a severe childhood epilepsy.
These findings intrigued Chao Tai, PhD, a scientist on Mucke's team and first author of the new paper, who had previously studied Dravet syndrome at the University of Washington.
"We wondered whether tau reduction could also prevent the signs of autism that are often seen in people with Dravet syndrome," Tai said.
To explore this possibility, the team investigated a mouse model of Dravet syndrome after deleting one or both copies of the gene that encodes tau. They found that reducing tau indeed prevented the development of core autism symptoms in this model. Even 50 percent reduction of tau showed major benefits.
Because the causes of autism are so diverse, the researchers next tested the effect of tau reduction in a second mouse model of autism that results from a very different genetic mutation.
Sure enough, "it also worked beautifully," Tai said. "The autism-like behaviors were again strongly suppressed by tau reduction."
Tau reduction also prevented epilepsy, as well as two additional abnormalities seen in people with autism and related mouse models: an enlargement of the brain known as megalencephaly, and over-activation of the PI3K-Akt-mTOR signaling pathway, which regulates many important cell functions.
Finally, the researchers investigated the molecular mechanisms by which tau reduction prevents these abnormalities. They found that tau reduction enhances the activity of a powerful enzyme called PTEN, which can prevent overactivation of the autism-promoting signaling pathway.
Addressing a Dire Need for Novel Treatments
The new findings highlight the potential of tau reduction to counteract both neurologic and psychiatric disorders. "Tau reduction appears to be the first strategy that can prevent both autism and epilepsy, two challenging conditions that all too often afflict the same people," Mucke said.
"Autism is very frequent, affecting roughly one in 60 children," Tai said. "Our findings could help address the urgent need for the development of better therapeutic strategies."
However, as the paper also demonstrates, tau reduction will probably not be effective against all forms of autism, and more research would be needed to determine exactly who might benefit.
In addition, the alterations that cause autism likely affect the brain during early stages of development and well before the diagnosis is typically made. "We are therefore eager to investigate whether tau reduction can also reverse symptoms of autism after they have emerged," Mucke said. "Ongoing studies in experimental models should help clarify optimal times for administering tau-lowering drugs to prevent or treat symptoms."
Mucke and colleagues are developing and testing small-molecule drugs that could lower tau levels or increase the activity of PTEN. Other investigational tau-lowering approaches are already being tested in people as a potential treatment for Alzheimer's disease, and this new research suggests that findings from those trials may also be informative in regard to autism.
About the Research Project
The National Institutes of Health and the Tau Consortium provided funding for this research. Other authors include Che-Wei Chang, Gui-Qiu Yu, Isabel Lopez, Xinxing Yu, Xin Wang, and Weikun Guo from the Gladstone Institutes.
About the Gladstone Institutes
To ensure our work does the greatest good, the Gladstone Institutes focus on conditions with profound medical, economic, and social impact—major unsolved diseases. Gladstone is an independent, nonprofit life science research organization that uses visionary science and technology to overcome disease. It has an academic affiliation with the University of California, San Francisco.
Media Contact: Megan McDevitt | Science Writer and PR Specialist | [email protected] | 415.734.2019
SOURCE Gladstone Institutes
现在， GladstonInstitutes 的研究人员在 Neuron 上报告说，降低一种叫做 tau 的蛋白质水平可以防止模拟各种自闭症谱系障碍的老鼠模型中出现的核心症状。这些小鼠的 Tau 减少也可以防止癫痫发作，这在30%的自闭症患者中发生。
“我们的发现表明， tau 的减少有希望成为某种形式的自闭症的潜在治疗，” LennartMucke 医学博士说， Gladstone 神经疾病研究所的创始主任和新论文的资深作者。
这些令人惊讶的发现源于对阿尔茨海默氏症和癫痫之间联系的调查。最初， Mucke 和他的同事们发现， tau 的减少可以防止老年痴呆症和严重的儿童癫痫病 Drawvesyndrome 小鼠模型中的癫痫活动和认知缺陷。
这些发现引起了赵泰博士的兴趣，他是 Mucke 团队的科学家，也是新论文的第一作者，之前曾在华盛顿大学研究过 Drawvesyndrome 。
“我们想知道 tau 的减少是否也能防止患有 Drawvesyndrome 的人经常看到的自闭症症状，” Tai 说。
为了探讨这种可能性，研究小组在删除了编码 tau 的基因的一个或两个副本之后，研究了 Drawvesyndrome 的老鼠模型。他们发现，减少 tau 确实阻止了核心自闭症症状的发展。甚至50%的牛头减少显示出主要的好处。
由于自闭症的原因是如此多样，研究者们接下来测试了另一种由不同基因突变引起的自闭症小鼠模型中 tau 减少的影响。
“当然足够了，”他说。“类似自闭症的行为再次被 tau 减少强烈抑制。”
牛黄还能预防癫痫，以及自闭症患者和相关小鼠模型中出现的两种额外的异常：大脑的放大即巨量脑功能，以及 PI3K-Akt-mTOR 信号通路的过度激活，这些信号通路调节许多重要的细胞功能。
最后，研究人员研究了牛磺酸还原防止这些异常的分子机制。他们发现 tau 的减少增强了一种叫做 PTEN 的强大酶的活性，它可以防止自闭症促进信号通路过度激活。
新的发现突出了 tau 减少的潜力，以抵消神经和精神疾病。“ Tau 的减少似乎是第一个既能预防自闭症又能预防癫痫的策略，这两种具有挑战性的条件都经常困扰着同一个人，” Mucke 说。
然而，正如论文还表明的， tau 的减少可能不会有效地对抗所有形式的自闭症，需要更多的研究来确定谁可能受益。
此外，导致自闭症的改变可能会影响大脑发育的早期阶段和诊断之前很久典型。Mucke 说：“因此，我们迫切希望研究 tau 的减少是否也能在自闭症症状出现后逆转。”“正在进行的实验模型研究应该有助于澄清服用降低牛磺酸的药物预防或治疗症状的最佳时机。”
Mucke 和他的同事正在开发和测试可以降低 tau 水平或增加 PTEN 活性的小分子药物。其他的研究降低偏头痛的方法已经在人们中进行测试，作为一种潜在的治疗老年痴呆症的方法，这一新的研究表明，这些试验的结果也可能是有益的关于孤独症。
美国国立卫生研究院和 Tau 联合会为这项研究提供了资金。其他作者包括来自 Gladstone 研究所的 Che-WeiChang 、 Gui-Qiu Yu 、 Isabel Lopez 、 Xixing Yu 、 Xin Wang 和 Weikun Guo 。
关于 Gladstone 研究所
为了确保我们的工作做得最好， GladstonInstitutes 专注于医学、经济和社会影响深远的疾病——主要未解决的疾病。Gladstone 是一个独立的、非营利性的生命科学研究组织，利用富有远见的科学技术来克服疾病。它与旧金山加利福尼亚大学有学术联系。
媒体联系人： Megan McDevitt | Science Writer 和 PR Specialist |[受电子邮件保护]||||415.734.2019