Complementary roles of the neuron-enriched endosomal proteins NEEP21 and calcyon in neuronal vesicle trafficking

Understanding mechanisms governing the trafficking of transmembrane (TM) cargoes to synapses and other specialized membranes in neurons represents a long-standing challenge in cell biology. Investigation of the neuron-enriched endosomal protein of 21 kDa (NEEP21, or NSG1or P21) and Calcyon (Caly, or NSG3) indicates that the emergence of the NEEP21/Caly/P19 gene family could play a vital role in the success of these mechanisms in vertebrates. The upshot of a sizeable body of work is that the NEEP21 and Caly perform distinct endocytic and recycling functions, which impact (i) α amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptor trafficking at excitatory synapses; (ii) transport to/in neuronal axons; as well as (iii) proteolytic processing of amyloid precursor protein and neuregulin 1, suggesting roles in neuron development, synaptic function, and neurodegeneration. We argue that their distinct effects on cargo endocytosis and recycling depend on interactions with vesicle trafficking and synaptic scaffolding proteins. As they play complementary, but opposing roles in cargo endocytosis, recycling, and degradation, balancing NEEP21 and Caly expression levels or activity could be important for homeostasis in a variety of signaling pathways, and also lead to a novel therapeutic strategy for disorders like Alzheimer's disease and schizophrenia. This review focuses on two closely related, neuron-enriched endosomal proteins: NEEP21 and Calcyon which perform distinct roles in regulating receptor endocytosis, recycling, and degradation. Based on an in-depth examination of the literature, we argue that these two proteins carry out complementary yet sometimes opposing vesicle trafficking functions that impact excitatory transmission, transcytosis, axonal transport, and also proteolytic processing by beta-secretase I (BACE1). Finally, we propose that balancing NEEP21 and Calcyon expression and/or activity could be important for homeostasis in a variety of signaling pathways, and also lead to a novel therapeutic strategy for disorders like Alzheimer's disease and schizophrenia. AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; NMDA = N-Methyl-D-aspartate.