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Project
Structural and functional characterization of the dual activity lipid phosphatase Synaptojanin 1 and its validation as a new drug target for intractable epilepsy (FWOSB78)
Synaptojanin 1 (Synj1) is an enzyme enriched at the nerve endings of the human brain where it functions as a lipid phosphatase acting upon signalling lipids called phosphoinositides or PIPs. The enzyme bears two catalytic domains: a Sac domain that predominantly dephosphorylates PI(3)P and PI(4)P, and a 5-phosphatase (5- PPase) domain dephosphorylating PI(4,5)P2 and PI(3,4,5)P3 at the
5’ position of the inositol ring.
Upregulation of Synj1 has previously been associated with Alzheimer’s disease and learning deficits in Down syndrome, while mutations in its Sac domain lead to Parkinson’s disease. Recently, we identified the 5-PPase domain of Synj1 as a very attractive target to treat certain types of epilepsy. However, insights in the disease
mechanisms at atomic scale and the development of potent inhibitors specifically targeting the Synj1 5-PPase domain are impeded by the lack of structural data and detailed biophysical / kinetic studies. Therefore, this project aims to obtain detailed understanding in the structure and working mechanisms of Synj1 and the effect of the disease-associated mutations. Subsequently, we will use these structural and functional insights to develop, test and validate the first specific inhibitors of Synj1 5-PPase activity, with potential therapeutic applications not only in epilepsy but on the longer term possibly also in Alzheimer’s disease. .
5’ position of the inositol ring.
Upregulation of Synj1 has previously been associated with Alzheimer’s disease and learning deficits in Down syndrome, while mutations in its Sac domain lead to Parkinson’s disease. Recently, we identified the 5-PPase domain of Synj1 as a very attractive target to treat certain types of epilepsy. However, insights in the disease
mechanisms at atomic scale and the development of potent inhibitors specifically targeting the Synj1 5-PPase domain are impeded by the lack of structural data and detailed biophysical / kinetic studies. Therefore, this project aims to obtain detailed understanding in the structure and working mechanisms of Synj1 and the effect of the disease-associated mutations. Subsequently, we will use these structural and functional insights to develop, test and validate the first specific inhibitors of Synj1 5-PPase activity, with potential therapeutic applications not only in epilepsy but on the longer term possibly also in Alzheimer’s disease. .
Date:1 Nov 2019 → 31 Oct 2023
Keywords:Protein structure-function
Disciplines:Proteins