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Mol. Psychiatr., Sep 06 2024, | https://doi.org/10.1038/s41380-024-02741-z
Impaired macroautophagy confers substantial risk for intellectual disability in children with autism spectrum disorders
Ahrom Ham1, Audrey Yuen Chang1, Hongyu Li1, Jennifer M. Bain1, James E. Goldman2, David Sulzer3,4,5, Jeremy Veenstra-VanderWeele3,5 and Guomei Tang1
1Department of Neurology, Columbia University Irving Medical Center, New York, NY 10032, USA.
2Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA.
3Department of Psychiatry, Columbia University Irving Medical Center, New York, NY 10032, USA.
4Department of Pharmacology, Columbia University Irving Medical Center, New York, NY 10032, USA.
5New York State Psychiatric Institute, New York, NY 10032, USA.
Corresponding author
Correspondence to Guomei Tang.
Abstract
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.
논문정보
- Research article
- 2024년 09월 (BRIC 등록일 2024-09-11)
- 국외 연구진
- 의약학 > 신경의학
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