THESIS
2011
xi leaves, 107 p. : ill. (chiefly col.) ; 30 cm
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...[
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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.
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