Role of neuroligin in neuronal secretory pathway

Abstract

The neuroligins are a family of postsynaptic transmembrane proteins that associate specifically with their presynaptic partners, beta-neurexins. This trans-synaptic interaction has been extensively studied in formation, stability and maturation of synapses in central nervous system. Recent studies reported that mutations of neuroligin, especially neuroligin (NLGN) 3 and 4, were found in siblings with autism spectrum disorder. Nonetheless, the molecular mechanisms on how such mutations disrupt the normal neurological development and hence result in these lifetime cognitive and social disabilities are still unknown. Mice carry the point mutation that substituted a Cys for Arg451 of NLGN3, which mimic the mutation found in human autistic patients, also display autism-like behaviors. We revealed that neuroligins mediated the down-regulation of chromogranin A (CGA) and brain-derived neurotrophic factor (BDNF) secretion in over-expression system. Logically, lentiviral shRNA-mediated knockdown of NLGN3 markedly up-regulated the expression of CGA in cultured neuron. Acute knockdown experiment has implied that neuroligin 3 play a role as negative regulator of secretion evidenced by dense-core vesicle marker CGA. Later, it has been found that acute suppression of other endogenous neuroligin besides NLGN3 also resulted in enhancement of CGA in NLGN1 knockdown, indicating an extent degree of functional redundancy among neuroligin members in regulating this pathway. This redundancy is a possible explanation for the observation that there was no significant difference in CGA and BDNF level detected in NLGN3 knockout mice. Interestingly, the Cys mutation caused intracellular retention of NLGN3 and defective trafficking, leading to abolishment of membrane localization. Co-expression with this NLGN3 mutant induced accumulation of CGA and BDNF in Golgi region evidenced by the formation of large aggregates. Taking together, these insights in the novel function of neuroligins may help to identify new pathways affected in autistic patients. In particular, it may suggest that deficit in functionality of dense-core vesicles, which contain neurotrophins, neuropeptides and monoamines, might contribute to the pathogenesis of autism in a subgroup of patients.

Date of Award	2011
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology