近日，美国耶鲁大学教授Kristopher T. Kahle及其研究组报道了PTEN突变通过失调脑室周围神经祖细胞损害脑脊液动力学和皮质网络。这一研究成果发表在2025年2月24日出版的国际学术期刊《自然—神经科学》上。

课题组人员发现自闭症风险基因PTEN的新生突变是CH和原发性脑室肥大最常见的单基因突变之一。脑室周围Nkx2.1⁺神经祖细胞（NPCs）过度增生和增殖性脉络膜丛脑脊液产量增加导致的导水管狭窄导致Motheme-pten突变型脑室增大。由于Nkx2.1⁺ NPC衍生的抑制性中间神经元活性增加，PTEN突变的脑室大皮质表现出网络功能障碍。Raptor缺失或出生后依维肟治疗可纠正脑室肥大，挽救皮质缺陷，并通过拮抗mTORC1依赖性Nkx2.1⁺ NPC病理提高生存率。它们，PTEN突变同时通过失调Nkx2.1⁺ NPC改变脑脊液动力学和皮质网络。这些结果表明脑室肥大和ASD存在遗传关联，并有助于解释脑室肥大患者脑脊液分流难的神经发育表型。

据了解，充满脑脊液（CSF）的脑室增大（脑室肿大）是先天性脑积水（CH）的典型特征，也是自闭症的一种未被充分认识的伴随症状。

附：英文原文

Title: PTEN mutations impair CSF dynamics and cortical networks by dysregulating periventricular neural progenitors

Author: DeSpenza, Tyrone, Kiziltug, Emre, Allington, Garrett, Barson, Daniel G., McGee, Stephen, OConnor, David, Robert, Stephanie M., Mekbib, Kedous Y., Nanda, Pranav, Greenberg, Ana B. W., Singh, Amrita, Duy, Phan Q., Mandino, Francesca, Zhao, Shujuan, Lynn, Anna, Reeves, Benjamin C., Marlier, Arnaud, Getz, Stephanie A., Nelson-Williams, Carol, Shimelis, Hermela, Walsh, Lauren K., Zhang, Junhui, Wang, Wei, Prina, Mackenzi L., OuYang, Annaliese, Abdulkareem, Asan F., Smith, Hannah, Shohfi, John, Mehta, Neel H., Dennis, Evan, Reduron, Laetitia R., Hong, Jennifer, Butler, William, Carter, Bob S., Deniz, Engin, Lake, Evelyn M. R., Constable, R. Todd, Sahin, Mustafa, Srivastava, Siddharth, Winden, Kellen, Hoffman, Ellen J., Carlson, Marina, Gunel, Murat, Lifton, Richard P., Alper, Seth L., Jin, Sheng Chih, Crair, Michael C., Moreno-De-Luca, Andres, Luikart, Bryan W., Kahle, Kristopher T.

Issue&Volume: 2025-02-24

Abstract: Enlargement of the cerebrospinal fluid (CSF)-filled brain ventricles (ventriculomegaly) is a defining feature of congenital hydrocephalus (CH) and an under-recognized concomitant of autism. Here, we show that de novo mutations in the autism risk gene PTEN are among the most frequent monogenic causes of CH and primary ventriculomegaly. Mouse Pten-mutant ventriculomegaly results from aqueductal stenosis due to hyperproliferation of periventricular Nkx2.1⁺ neural progenitor cells (NPCs) and increased CSF production from hyperplastic choroid plexus. Pten-mutant ventriculomegalic cortices exhibit network dysfunction from increased activity of Nkx2.1⁺ NPC-derived inhibitory interneurons. Raptor deletion or postnatal everolimus treatment corrects ventriculomegaly, rescues cortical deficits and increases survival by antagonizing mTORC1-dependent Nkx2.1⁺ NPC pathology. Thus, PTEN mutations concurrently alter CSF dynamics and cortical networks by dysregulating Nkx2.1⁺ NPCs. These results implicate a nonsurgical treatment for CH, demonstrate a genetic association of ventriculomegaly and ASD, and help explain neurodevelopmental phenotypes refractory to CSF shunting in select individuals with CH.

DOI: 10.1038/s41593-024-01865-3

Source: https://www.nature.com/articles/s41593-024-01865-3