Ham Ahrom, Chang Audrey Yuen, Li Hongyu, Bain Jennifer M, Goldman James E, Sulzer David, Veenstra-VanderWeele Jeremy, Tang Guomei
Department of Neurology, Columbia University Irving Medical Center, New York, NY, 10032, USA.
Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, 10032, USA.
Mol Psychiatry. 2025 Feb;30(2):810-824. doi: 10.1038/s41380-024-02741-z.
Autism spectrum disorder (ASD) represents a complex of neurological and developmental disabilities characterized by clinical and genetic heterogeneity. While the causes of ASD are still unknown, many ASD risk factors are found to converge on intracellular quality control mechanisms that are essential for cellular homeostasis, including the autophagy-lysosomal degradation pathway. Studies have reported impaired autophagy in ASD human brain and ASD-like synapse pathology and behaviors in mouse models of brain autophagy deficiency, highlighting an essential role for defective autophagy in ASD pathogenesis. To determine whether altered autophagy in the brain may also occur in peripheral cells that might provide useful biomarkers, we assessed activities of autophagy in lympoblasts from ASD and control subjects. We find that lymphoblast autophagy is compromised in a subset of ASD participants due to impaired autophagy induction. Similar changes in autophagy are detected in postmortem human brains from ASD individuals and in brain and peripheral blood mononuclear cells from syndromic ASD mouse models. Remarkably, we find a strong correlation between impaired autophagy and intellectual disability in ASD participants. By depleting the key autophagy gene Atg7 from different brain cells, we provide further evidence that autophagy deficiency causes cognitive impairment in mice. Together, our findings suggest autophagy dysfunction as a convergent mechanism that can be detected in peripheral blood cells from a subset of autistic individuals, and that lymphoblast autophagy may serve as a biomarker to stratify ASD patients for the development of targeted interventions.
自闭症谱系障碍（ASD）是一种神经和发育障碍的综合体，其特征在于临床和遗传异质性。虽然ASD的病因仍然未知，但许多ASD风险因素被发现集中在对细胞内稳态至关重要的细胞内质量控制机制上，包括自噬 - 溶酶体降解途径。研究报告了ASD人脑自噬受损以及脑自噬缺陷小鼠模型中类似ASD的突触病理学和行为，突出了自噬缺陷在ASD发病机制中的重要作用。为了确定大脑中自噬的改变是否也可能发生在外周细胞中，而外周细胞可能提供有用的生物标志物，我们评估了ASD患者和对照受试者的淋巴母细胞中的自噬活性。我们发现，由于自噬诱导受损，一部分ASD参与者的淋巴母细胞自噬受到损害。在ASD个体的死后人类大脑以及综合征性ASD小鼠模型的大脑和外周血单核细胞中也检测到了类似的自噬变化。值得注意的是，我们发现ASD参与者中自噬受损与智力残疾之间存在强烈相关性。通过从不同脑细胞中敲除关键自噬基因Atg7，我们进一步证明自噬缺陷会导致小鼠认知障碍。总之，我们的研究结果表明自噬功能障碍是一种可在一部分自闭症个体的外周血细胞中检测到的汇聚机制，并且淋巴母细胞自噬可能作为一种生物标志物，用于对ASD患者进行分层，以开发针对性的干预措施。
