Research Topic

Within the last decade of neurobiology, liquid-liquid phase separation (LLPS) has gained increasing attention in organising the postsynaptic density (PSD) and the presynaptic active zone. Neuronal scaffold proteins are known to form liquid-liquid phase separated nanoclusters within postsynaptic protein network through versatile interactions, with four neuronal scaffold proteins (e.g. GKAP, Shank3, Homer3, and PSD-95) acting as the key “drivers” for the condensed PSD assemblies. Although many members of the neuronal scaffold proteins have been already well-described, their exact functions and importance in the formation of LLPS are not yet fully known. Additionally, unbalanced of LLPS of neuronal scaffold proteins is linked to protein dysfunction associated with major neurodevelopmental disorders (autism spectrum disorder and attention deficit hyperactivity disorder). These disorders of social behaviour and communication are increasingly prevalent and pose a substantial burden to society. 

Caskin1 neuronal scaffold proteins is expressed at high levels in the brain, mainly in the synaptic regions. We have recently shown that these proteins play a previously unnoticed role in synaptic plasticity and memory formation by regulating activity-dependent morphological rearrangement of dendritic spines. Our work was the first to address Caskin-mediated effects within the postsynaptic protein network. N-terminal region of Caskin1 contains several well-known functional domains, but a very high part (57.9 %) of Caskin1 protein is formed by intrinsically disordered regions (IDRs). Intrinsically disordered proteins that lack a well-defined folded structure, have been shown to participate in LLPS. Additionally, based on literature data, appearance of IDRs has been implicated in several neurodevelopmental disorders. Currently, given the potential importance of Caskin scaffold proteins in neurodevelopmental disorders, we are characterizing in detail the social behaviour and repetitive behaviours in mice. 

Based on structural information and bioinformatics predictions, it is likely that Caskin1 interactions also depend on LLPS, however, experimental evidence for full details is pending. In line with its predicted LLPS propensity, our preliminary data show that purified wild-type Caskin1 form liquid-like condensates in vitro, but the molecular determinants driving this interaction are not yet fully understood. We therefore intend to demonstrate that Caskin1 is concentrated in the phase separated postsynaptic nanoclusters.

Research Topics

• (i) identify neuronal scaffold proteins bound by Caskin1 proteins that may have a role in neurodevelopmental disorders,
• (ii) prove that Caskin1-mediated functions within the PSD are linked to LLPS, as well as
• (iii) better understand of how Caskin1 regulates maintenance of postsynaptic density in neurons.

Taken together, the specific aim of our project is to demonstrate that Caskin1-mediated functions within the PSD are associated with LLPS. The results of the proposed study will provide novel insights into function of Caskin1 in postsynaptic protein network, and in a broader context, how the liquid-like features of postsynaptic density are altered during neurodevelopmental disorders. 

Scientific Contacts

Prof. Dr. Angelika Hausser  - Institute of Cellbiology and Immunology, University of Stuttgart, Germany