Pluto Bioinformatics

GSE80312: PTCHD1, a neurodevelopmental disorder-associated gene, contributes to glutamatergic neurotransmission through interaction with SAP102 and PSD95

Bulk RNA sequencing

Neuronal activity and synapse development represent fundamental processes for the establishement of cognitive function and communication1,2. The synapse structural organization as well as signaling pathways from receptor stimulation to gene expression regulation are mediated by synaptic activity and are targeted in neurodevelopmental diseases3,4,5. Mutations in the PTCHD1 gene have been described in patients with intellectual disability (ID) and/or autism spectrum disorder (ASD) but the neurodevelopmental role of PTCHD1 protein is unknown6. Here we report that PTCHD1 extensively regulates synaptic transcript abundance and that its deletion results in impaired cognitive function, hyperactivity and altered synaptic activity in Ptchd1 deficient mice. We also characterized a functional PDZ-domain binding site at the C-terminal end of PTCHD1 protein sequence that can specifically bind postsynaptic proteins PSD95 and SAP102, similarly to EXOC4, Neuroligins and NMDA receptors7,8,9. Lastly, we provide evidence that PTCHD1 does not modulate Gli gene expression, suggesting that PTCHD1 acts in a non-canonical Hedgehog signaling pathway directly associated with postsynaptic membrane-associated proteins to regulate synapse organization and function. In conclusion, the PTCHD1 receptor describes a novel neuronal pathway linking Hedgehog to the functional organization of glutamatergic synapses by closely regulating synaptic transcriptome expression level. SOURCE: giovanni iaconoHenk Stunnenberg Radboud Institute for Molecular Life Sciences