Through this multidisciplinary project, we aim to gain fundamental insights into the cellular biology and biochemistry of PTCHD1 relevant to autism spectrum disorder (ASD), a neurodevelopmental condition characterised by eg, restricted interests and atypical social interaction. The PTCHD1 protein plays a crucial role in neurodevelopment and plasticity, and mutations in it underlie up to 1% of ASD cases. However, its biochemistry and -physics, the link between its activity and neurodevelopment, the cellular effect of mutations, and its connection to Fragile X syndrome is not understood. To gain mechanistic insight, we will determine the structure of human PTCHD1 by single particle cryo-electron microscopy. Then, to establish its function, we will study its cholesterol transport activity and investigate how the C-terminus regulates its stability and localisation to the synapse. Finally, we will follow up brand new insights suggesting how PTCHD1 is linked to Fragile X syndrome.

2023

2027