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Synaptojanin 1 (SJ1) is a major presynaptic phosphatase that couples synaptic vesicle endocytosis to the dephosphorylation of PI(4,5)P2, a reaction needed for the shedding of endocytic factors from their membranes. While the role of SJ1's 5-phosphatase module in this process is well recognized, the contribution of its Sac phosphatase domain, whose preferred substrate is PI4P, remains unclear. Recently a homozygous mutation in its Sac domain was identified in early-onset parkinsonism patients. We show that mice carrying this mutation developed neurological manifestations similar to those of human patients. Synapses of these mice displayed endocytic defects and a striking accumulation of clathrin-coated intermediates, strongly implicating Sac domain's activity in endocytic protein dynamics. Mutant brains had elevated auxilin (PARK19) and parkin (PARK2) levels. Moreover, dystrophic axonal terminal changes were selectively observed in dopaminergic axons in the dorsal striatum. These results strengthen evidence for a link between synaptic endocytic dysfunction and Parkinson's disease.

Mutations that alter signaling through the mammalian target of rapamycin complex 1 (mTORC 1 ), a well established regulator of neuronal protein synthesis, have been linked to autism and cognitive dysfunction. Although previous studies have established a role for mTORCl as necessary for enduring changes in postsynaptic function, here we demonstrate that dendritic mTORCl activation in rat hippocampal neurons also drives a retrograde signaling mechanism promoting enhanced neurotransmitter release from apposed presynaptic termi-nals. This novel mode of synaptic regulation conferred by dendritic mTORCl is locally implemented, requires downstream synthesis of brain-derived neurotrophic factor as a retrograde messenger, and is engaged in an activity-dependent fashion to support homeostatic fraiis-synaptic control of presynaptic function. Our findings thus reveal that mTORCl-dependent translation in dendrites subserves a unique mode of synaptic regulation, highlighting an alternative regulatory pathway that could contribute to the social and cognitive dysfunction that accompanies dysregulated mTORCl signaling. [ABSTRACT FROM AUTHOR]

Normal steady-state levels of the signalling lipids PI(3,5)P2 and PI(5)P require the lipid kinase FAB1/PIKfyve and its regulators, VAC14 and FIG4. Mutations in the PIKfyve/VAC14/FIG4 pathway are associated with Charcot-Marie-Tooth syndrome and amyotrophic lateral sclerosis in humans, and profound neurodegeneration in mice. Hence, tight regulation of this pathway is critical for neural function. Here, we examine the localization and physiological role of VAC14 in neurons. We report that endogenous VAC14 localizes to endocytic organelles in fibroblasts and neurons. Unexpectedly, VAC14 exhibits a pronounced synaptic localization in hippocampal neurons, suggesting a role in regulating synaptic function. Indeed, the amplitude of miniature excitatory postsynaptic currents is enhanced in both Vac14?/? and Fig4?/? neurons. Re-introduction of VAC14 in postsynaptic Vac14?/? cells reverses this effect. These changes in synaptic strength in Vac14?/? neurons are associated with enhanced surface levels of the AMPA-type glutamate receptor subunit GluA2, an effect that is due to diminished regulated endocytosis of AMPA receptors. Thus, VAC14, PI(3,5)P2 and/or PI(5)P play a role in controlling postsynaptic function via regulation of endocytic cycling of AMPA receptors. [ABSTRACT FROM AUTHOR]