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Impaired macroautophagy confers substantial risk for intellectual disability in children with autism spectrum disorders

Molecular Psychiatry volume 30, pages 810–824 (2025)Cite this article

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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.

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Fig. 1: Autophagy signaling pathway and ASD.
Fig. 2: Aberrant autophagy in ASD lymphoblasts.
Fig. 3: Dysregulated Autophagy in ASD lymphoblasts from the Simons Simplex Collection (SSC).
Fig. 4: Altered autophagic flux in SSC ASD lymphoblasts.
Fig. 5: Levels of autophagy regulatory proteins in ASD human postmortem brains and syndromic ASD mouse models.
Fig. 6: Autophagy deficiency in various brain cells causes cognitive impairment.

Data availability

Raw data and patient demographic information are presented in supplementary tables that are specifically associated with each figure and will be available from the corresponding author upon request.

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Acknowledgements

We thank the Coriell Institute for Medical Research and the Simons Simplex Collection (SSC) for patient derived lymphoblasts and the University of Maryland Brain and Tissue Bank and Harvard Brain Tissue Resource Center for human brain specimens.

Funding

This work was supported by the NIMH K01 award (K01 MH096956), the Simons Foundation Autism Research Initiative Pilot Award (SFARI 402220) and the Defense Health Programs and Congressionally Directed Medical Research Programs through the TSCRP under Awards W81XWH-16-1-0263.

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Authors and Affiliations

  1. Department of Neurology, Columbia University Irving Medical Center, New York, NY, 10032, USA

    Ahrom Ham, Audrey Yuen Chang, Hongyu Li, Jennifer M. Bain & Guomei Tang

  2. Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, 10032, USA

    James E. Goldman

  3. Department of Psychiatry, Columbia University Irving Medical Center, New York, NY, 10032, USA

    David Sulzer & Jeremy Veenstra-VanderWeele

  4. Department of Pharmacology, Columbia University Irving Medical Center, New York, NY, 10032, USA

    David Sulzer

  5. New York State Psychiatric Institute, New York, NY, 10032, USA

    David Sulzer & Jeremy Veenstra-VanderWeele

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Contributions

GT and JV designed the project, selected participants, and wrote the paper. AH, AYC and HL conducted behavioral phenotyping, biochemical and imaging analysis in human lymphoblasts, human and mouse brains. DS, JEG and JB provided critical feedback and shaped the research, data interpretation and manuscript preparation.

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Correspondence to Guomei Tang.

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The authors declare no competing interests.

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All experiments were performed in accordance with the relevant guidelines and regulations. The use of deidentified human lymphoblast cell lines and postmortem brains was reviewed by the institutional review boards of Columbia University Irving Medical Center and was determined to be “Not Human Subjects Research Under 45 CFR 46”. No IRB approval or informed consent was required. All procedures on mice were reviewed and approved by the Institutional Animal Care and Use Committee at Columbia University Irving Medical Center.

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Ham, A., Chang, A.Y., Li, H. et al. Impaired macroautophagy confers substantial risk for intellectual disability in children with autism spectrum disorders. Mol Psychiatry 30, 810–824 (2025). https://doi.org/10.1038/s41380-024-02741-z

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