Biology subjects

Chiocchetti, A.

Publications and source records attributed to Chiocchetti, A..

3 recordsLinked to original sources

bioRxiv2025

Inhibition of the neurodevelopmental disorder-associated 16p11.2 gene QPRT leads to altered cell type distribution in human stem cell-derived cerebral organoids

The 16p11.2 gene QPRT, encoding a key enzyme of the kynurenine pathway, has been linked to neurodevelopmental disorders including autism spectrum disorder (ASD). To investigate its role in early human brain development, we inhibited QPRT in stem cell-derived cerebral organoids. QPRT inhibition resulted in reduced organoid size, driven by premature neural differentiation resulting in depleted progenitor populations. Single-cell transcriptomics revealed an excitation/inhibition imbalance, with reduced excitatory and increased inhibitory neuron populations. We observed metabolic stress signatures, including pseudo-hypoxia, oxidative stress, and mitochondrial dysfunction, likely linked to NAD+ depletion and QUIN accumulation following QPRT inhibition. Notably, downregulation of LHX2 and PRDX1 may underlie impaired neural patterning and excitotoxic vulnerability. In addition, we report astrocytic and radial glia dysfunctions, indicating broad effects across multiple cell types. Disease gene enrichment analyses showed significant overlap with ASD-associated genes, especially during early differentiation. These findings suggest the loss or reduction of QPRT to shift neural development and neuronal homeostasis towards an imbalance in excitatory and inhibitory neuronal populations, a mechanism previously associated with neurodevelopmental disorders.

cell biology↗

bioRxiv2025

Expression profile of the ADHD risk gene ADGRL3 during human neurodevelopment and the effects of genetic variation

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders, affecting [~]5.3 % children, with symptoms including hyperactivity, inattention and impulsivity. Moreover, ADHD persists into adulthood in [~]50 % cases, significantly affecting quality of life. Currently, the complex aetiology of ADHD remains unclear, although it has been shown that it is a highly heritable disorder. Single nucleotide polymorphisms (SNPs) in the adhesion G protein-coupled receptor isoform L3 gene (ADGRL3/ LPHN3) have been consistently associated with ADHD development, symptom severity and treatment response, with the rs1397547 SNP previously shown associated with altered ADGRL3 transcription. Animal models have revealed an essential role of ADGRL3 in glutamatergic synapse development. However, ADGRL3 function has not been investigated in humans. We used human induced pluripotent stem cell (hiPSC)-derived cortical neurons to characterise ADGRL3 expression during human neurogenesis in vitro, and found that expression peaks early in neurodevelopment, consistent with in vivo data. ADGRL3 protein was found primarily expressed in glutamatergic neurons, and localised to growth cone-like structures, supporting a role in neurite outgrowth and glutamatergic synapse development. Lastly, using hiPSC-derived cortical neurons from healthy controls and ADHD patients, we investigated whether the rs1397547 SNP could affect ADGRL3 expression in cortical neurons. We found the rs1397547 SNP was associated with significantly increased ADGRL3 transcription in early neurodevelopmental stages. Moreover, single-cell RNA sequencing of maturing cortical neurons revealed a unique transcriptional profile in SNP carriers. Our results further implicate ADGRL3 in ADHD development and suggest that genetic variation may result in dysregulated glutamatergic neuron development.

neuroscience↗

bioRxiv2018

Novel genes for autism implicate both excitatory and inhibitory cell lineages in risk

We present the largest exome sequencing study to date focused on rare variation in autism spectrum disorder (ASD) (n=35,584). Integrating de novo and case-control variation with an enhanced Bayesian framework incorporating evolutionary constraint against mutation, we implicate 99 genes in ASD risk at a false discovery rate (FDR) [≤] 0.1. Of these 99 risk genes, 46 show higher frequencies of disruptive de novo variants in individuals ascertained for severe neurodevelopmental delay, while 50 show higher frequencies in individuals ascertained for ASD, and comparing ASD cases with disruptive mutations in the two groups shows differences in phenotypic presentation. Expressed early in brain development, most of the risk genes have roles in neuronal communication or regulation of gene expression, and 12 fall within recurrent copy number variant loci. In human cortex single-cell gene expression data, expression of the 99 risk genes is also enriched in both excitatory and inhibitory neuronal lineages, implying that disruption of these genes alters the development of both neuron types. Together, these insights broaden our understanding of the neurobiology of ASD.

genetics↗