For instance, the neuronal early endosome protein NEEP21 (originally identified as Neural Specific Gene 1, Nsg1; Sabéran-Djoneidi et al., 1998 and Sutcliffe Selleck OSI-906 et al., 1983) is expressed primarily in neurons and is found in an early endosomal population largely distinct from
EEA1-positive endosomes (Steiner et al., 2002). NEEP21 interacts with the SNARE protein syntaxin13 and localizes to rab4-positive but rab5-negative domains of early endosomes (Steiner et al., 2002). NEEP21-positive endosomes accumulate endocytosed L1/NgCAM adhesion molecules, as well as AMPA receptors (Steiner et al., 2005, Steiner et al., 2002 and Yap et al., 2008) and are involved in trafficking of multiple cargos (Alberi et al., 2005, Debaigt et al., 2004, Steiner et al., 2005, Steiner et al., 2002 and Yap et al., 2008). NEEP21 also binds to GRIP1, an interaction important for GluR2 trafficking (Steiner et al., 2005). Recently, NEEP21 was shown to interact with and affect proteolytic processing of βAPP Raf inhibitor review (Norstrom et al., 2010). The precise mode of NEEP21 action, the role of its interaction with syntaxin13, and what neuronal-specific role it might play are still unknown. Another neuronal-specific protein is GRASP-1, which is an effector of Rab4 and an important component of the molecular machinery that coordinates RE maturation in dendrites. GRASP-1 is also necessary for
AMPAR recycling, maintenance of spine morphology, and synaptic plasticity (Hoogenraad et al., 2010). It will be important to elucidate how these neuronal-specific components modify the canonical machinery to achieve neuron-specific functions. Some canonical endosomal regulators have specialized functions in neurons. For example, in nonneuronal cells members of the EHD family, EHD1-EHD4, regulate trafficking through early and recycling endosomes (Grant and Caplan, 2008). EHD1 associates Megestrol Acetate with pre-existing tubules in fibroblasts (Sharma et al., 2009), but in neurons tubular EHD1-containing
compartments are virtually absent. Rather, EHD1 colocalizes predominantly with round EEA1-positive EEs. Live imaging showed that EHD1 precedes EEA1 on EEs and often persists even after EEA1 has dissociated (Yap et al., 2010). Interestingly, in neurons EHD4 (also called pincher) and EHD1 are involved in endocytosis (Shao et al., 2002), rather than (or in addition to) recycling (Sharma et al., 2008). For instance, Nogo-A, a repulsive cue for axon growth cones, was shown to be endocytosed by an EHD4/pincher pathway (Joset et al., 2010). L1/NgCAM uses an EHD1/EHD4-dependent pathway for endocytosis. This pathway is cargo specific and cell type specific (Yap et al., 2010). EHD4 (possibly as a heterodimer with EHD1) thus mediates a specialized internalization pathway in neurons. Since EHD proteins interact with multiple trafficking regulators via their C-terminal EH domains (Naslavsky and Caplan, 2011), they regulate and coordinate recruitment and activation of other effectors classes, such as rabs (Jovic et al., 2010).