Basic Science and Pathogenesis.

Background: AD/ADRD diseases currently impact more than 6 million people in the US. Rare forms of AD/ADRD are caused directly and unambiguously by genetic mutations. However, most AD/ADRD burden is complex in etiology and thought to result from an interplay among multiple incompletely understood genetic, biochemical, lifestyle, environmental and psychosocial risk factors.

Parkinson Sac Domain Mutation in Synaptojanin 1 Impairs Clathrin Uncoating at Synapses and Triggers Dystrophic Changes in Dopaminergic Axons.

Synaptojanin 1 (SJ1) is a major presynaptic phosphatase that couples synaptic vesicle endocytosis to the dephosphorylation of PI(4,5)P, 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.

Activity-dependent PI(3,5)P2 synthesis controls AMPA receptor trafficking during synaptic depression.

Dynamic regulation of phosphoinositide lipids (PIPs) is crucial for diverse cellular functions, and, in neurons, PIPs regulate membrane trafficking events that control synapse function. Neurons are particularly sensitive to the levels of the low abundant PIP, phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2], because mutations in PI(3,5)P2-related genes are implicated in multiple neurological disorders, including epilepsy, severe neuropathy, and neurodegeneration. Despite the importance of PI(3,5)P2 for neural function, surprisingly little is known about this signaling lipid in neurons, or any cell type.

Phosphatidylinositol 3,5-bisphosphate: low abundance, high significance.

Recent studies of the low abundant signaling lipid, phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2 ), reveal an intriguingly diverse list of downstream pathways, the intertwined relationship between PI(3,5)P2 and PI5P, as well as links to neurodegenerative diseases. Derived from the structural lipid phosphatidylinositol, PI(3,5)P2 is dynamically generated on multiple cellular compartments where interactions with an increasing list of effectors regulate many cellular pathways. A complex of proteins that includes Fab1/PIKfyve, Vac14, and Fig4/Sac3 mediates the biosynthesis of PI(3,5)P2 , and mutations that disrupt complex function and/or formation cause profound consequences in cells.

Retrograde changes in presynaptic function driven by dendritic mTORC1.

Mutations that alter signaling through the mammalian target of rapamycin complex 1 (mTORC1), a well established regulator of neuronal protein synthesis, have been linked to autism and cognitive dysfunction. Although previous studies have established a role for mTORC1 as necessary for enduring changes in postsynaptic function, here we demonstrate that dendritic mTORC1 activation in rat hippocampal neurons also drives a retrograde signaling mechanism promoting enhanced neurotransmitter release from apposed presynaptic terminals. This novel mode of synaptic regulation conferred by dendritic mTORC1 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 trans-synaptic control of presynaptic function.

Modulation of synaptic function by VAC14, a protein that regulates the phosphoinositides PI(3,5)P₂ and PI(5)P.

Normal steady-state levels of the signalling lipids PI(3,5)P(2) 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.

Local presynaptic activity gates homeostatic changes in presynaptic function driven by dendritic BDNF synthesis.

Homeostatic synaptic plasticity is important for maintaining stability of neuronal function, but heterogeneous expression mechanisms suggest that distinct facets of neuronal activity may shape the manner in which compensatory synaptic changes are implemented. Here, we demonstrate that local presynaptic activity gates a retrograde form of homeostatic plasticity induced by blockade of AMPA receptors (AMPARs) in cultured hippocampal neurons. We show that AMPAR blockade produces rapid (<3 hr) protein synthesis-dependent increases in both presynaptic and postsynaptic function and that the induction of presynaptic, but not postsynaptic, changes requires coincident local activity in presynaptic terminals.