Getting the Disordered in Order: Exploring the Role of Intrinsically Disordered Proteins in Synaptic Vesicle Condensation

Summary

Studying synaptic transmission is a key focus in neuroscience. At the pre-synapse, synaptic proteins and vesicles cluster into condensates, which affect critical processes like exocytosis, protein recovery post vesicle fusion, endocytosis, and super pool exchange. Around 25% of all synaptic proteins feature intrinsically disordered regions (IDRs), indicating that a significant proportion of these proteins play a role during condensate formation. 

Our recent findings reveal that transmembrane synaptic proteins, apart from their normal known function, can be important for the regulation of condensates. Specifically, we show that vesicle-associated membrane protein 2 (VAMP2) modulates protein condensation of alpha-synuclein. Charge-charge interactions and lipid binding are essential for this process (Agarwal et al. 2024 Nat Cell Biol) and suggest that similar mechanisms may exist for other protein partners on the surface of synaptic vesicles (SV).

Project aims

This project aims to discover and characterize new SV condensates and elucidate their role in synaptic function. From our synaptome dataset (Lautenschlaeger 2022 Open Biol) we will evaluate protein interaction partners. These will be tested and validated through synthetic reconstitution of protein self-assembly.

Furthermore, to investigate these processes in neurons, we will generate CRISPR-edited i3 neuron lines, which will be differentiated into glutamatergic neurons (Fernandopulle et al. 2018 Curr Protoc Cell Biol) to test functional read outs like electrical and calcium activity and SV exo- and endocytosis. Finally, we will examine functional and disease-related protein variants. 

Significance: This project will make significant contributions to understand synaptic biology and promises to advance our comprehension of synaptic diseases that are linked to disordered protein regions and aberrant protein condensates, paving the way for new translational research avenues.

Contact details

Dr Janin Lautenschlaeger - jl865@cam.ac.uk

Opportunities

This project is open to applicants who want to do a:

• PhD