Roles in physiology and disease of the inositol phosphatase synaptojanin 1.

Synaptojanin 1 (Synj1) is a protein highly enriched in the nervous system which comprises tandemly arranged inositol 4-phosphatase and 5-phosphatase domains. Since its discovery as a synaptically enriched binding partner of SH3 domain containing proteins, Synj1 has been shown to be a key player in synaptic vesicle recycling via its property to couple the endocytic reaction to dephosphorylation of PI(4,5)P2, a determinant of plasma membrane identity. Beyond its well established role in synaptic vesicle traffic, Synj1 has housekeeping roles at the interface of endocytosis, receptor signaling and regulation of actin nucleation. It is essential for postnatal life, while partial loss-of-function mutations are responsible for early-onset Parkinsonism and epilepsy. Conversely Synj1 overexpression, such as due to gene duplication in Down syndrome, may also have a pathogenic role. Here I review current knowledge about Synj1's molecular and physiological functions and the role of its dysfunction in disease.