Transcriptomic Analysis Uncovers an Unfolded Protein Response in ADNP Syndrome.

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• Chromatin regulators are frequently mutated in autism spectrum disorders (ASDs).
• ADNP syndrome, caused by mutations in the activity-dependent neuroprotective protein (ADNP), leads to intellectual deficiency and developmental delays.
• Mechanisms underlying ADNP syndrome pathogenesis remain largely unclear.

Purpose of the Study:

• To investigate the functional consequences of ADNP mutations on gene expression and neurodifferentiation using patient-derived induced pluripotent stem cells (iPSCs).
• To explore the role of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in ADNP syndrome.

Main Methods:

• Generation of iPSCs from ADNP syndrome patients.
• Analysis of subcellular localization of mutant ADNP proteins.
• Transcriptional profiling to assess gene expression changes.
• Assessment of neurodifferentiation and cell survival.
• Measurement of ER stress markers and UPR activation.

Main Results:

• ADNP mutations can result in truncated ADNP proteins with aberrant subcellular localization.
• Widespread transcriptional deregulation was observed in all tested ADNP mutants.
• Mutants with truncated ADNP fragments exhibited ER stress, evidenced by UPR activation.
• Higher UPR activation correlated with more severe neurodifferentiation and survival defects.

Conclusions:

• Truncated ADNP proteins may induce ER stress, contributing to ADNP syndrome pathology.
• UPR activation could serve as a potential biomarker for ADNP syndrome severity.
• This finding may extend to other ASDs caused by mutations leading to truncated proteins.