Understanding the structure, function and mechanism of Synaptojanin1 in the context of neurological disease

Phosphoinositides (PIPs) are membrane lipids that play a role in
important cellular processes, including cell signaling, exo- and
endocytosis, and synaptic vesicle trafficking. Consequently, the PIP
levels in the cell are regulated by a variety of kinases and
phosphatases. Synaptojanin1 (Synj1) is a pre-synaptic enzyme,
containing two catalytic PIP phosphatase domains: the so-called
SAC1 and 5-PPase domains. Synj1 was identified as a potential drug
target for Alzheimer’s disease and Down syndrome, while loss-offunction mutations are associated with epilepsy and Parkinson’s
disease. Despite its involvement in a range of disorders, detailed
structural and mechanistic information regarding the enzyme is still
lacking. Within this project we will set out to solve the 3-dimensional
structures of Synj1 and its constituting domains, trapped in different
stages of their catalytic cycle. This information, in combination with
biochemical and biophysical studies, will be used to unravel the fine
details of the catalytic mechanism of both domains, the effect of
disease mutations, and the regulation of the inter-domain
communication. Based on these structural and mechanistic insights
we will devise new modulators of Synj1 activity, which could pave the
way for new innovative therapeutic strategies for Synj1-associated
neurological diseases. Finally, we will also study the protein-protein
interactions of Synj1 relevant for its role in autophagy and
Parkinson’s disease.