The molecular mechanism by which caspase effects are restricted to specific neuronal compartments (perhaps even specific synapses) is an important unanswered

question. Local breakdown of proteins—and selective Navitoclax purchase pruning of synapses—can additionally be achieved by spatiotemporal control of E3 ligase assembly. In Caenorhabditis elegans, localized inhibition of the assembly of an SCF complex through binding of core protein SKR-1 to a synaptic adhesion molecule, SYG-1, spares synapses from elimination ( Ding et al., 2007). It is unknown whether synapse elimination in mammals also relies on local regulation of E3 ubiquitin ligase. The morphological sculpting of certain synapses is regulated by an evolutionarily conserved RING domain E3 ligase Phr1 (also known as Highwire in Drosophila, and RPM-1 in C. elegans)

( Schaefer et al., 2000, Wan et al., 2000 and Zhen et al., 2000). In mammals, Phr1 functions to sculpt motor nerve terminals and is essential for formation of major CNS axon tracts ( Bloom et al., 2007). Interestingly, in mice, Phr1 is localized to the axonal shaft and excluded from growth cones, where the protein kinase DLK is restricted ( Lewcock et al., 2007). In the absence of Phr1, DLK aberrantly distributes to axons, leading to altered microtubule dynamics and axon-pathfinding deficits. Based on the reciprocal localization of DLK and Phr1, DLK was proposed as a Phr1 substrate, similar to the scenario in invertebrates ( Collins et al., 2006, Lewcock et al., 2007 and Nakata et al., 2005). However, no increase in DLK was detected Bortezomib in vivo in the central nervous system of Phr1 mutant mice and DLK is not required for Phr1 loss-of-function phenotypes ( Bloom et al., 2007). In fish, Phr1 localizes to growth cones and regulates pathfinding independent of DLK ( Hendricks and Jesuthasan, 2009). Collectively, these studies demonstrate that despite possible cell-type or species-specific differences

in the regulation of Phr1, this ubiquitin ligase regulates microtubule remodeling during development and is crucial for axon navigation. HECT domain Nedd4 is another ubiquitin ligase acting in axons; it promotes branching by targeting PTEN, a PIP3 phosphatase that negatively regulates axonal branching (Drinjakovic et al., 2010). Remarkably, Nedd4 also enhances Digestive enzyme the branching of dendrites by monoubiquitinating GTPase Rap2 and inhibiting its function (Kawabe et al., 2010). Thus an E3 ligase can target different substrates in different subcellular compartments to carry out similar cell biological functions. Neurons also utilize the lysosome system to degrade organelles and synaptic proteins. For example, following endocytosis, AMPARs either recycle back to the membrane or are sorted into lysosomes, depending on their subunit composition and whether AMPARs themselves or NMDARs were activated (Ehlers, 2000 and Lee et al., 2004).