Novel Interactive Partners of Neuroligin 3: New Aspects for Pathogenesis of Autism

Abstract

Autism is a neurodevelopmental disorder with a strong genetic predisposition. Neurolign 3 (NLGN3) as a postsynaptic transmembrane protein, functions in both neuron synaptogenesis and glia-neuron communications. Previously, a gain of function mutation (R451C) in NLGN3 was identified in autistic patients, which illustrates the involvement of NLGN3 in autism pathogenesis. As proper synaptic targeting and functioning are controlled by intracellular protein interactions, in the current study, we tried to discover the intracellular regulation network in which NLGN3 might be involved by a yeast two-hybrid-based interactor identification. Fifty-one protein candidate partners were identified after screening a human fetal complementary DNA (cDNA) library with an intracellular fragment of NLGN3. The interactions of NLGN3 with a subset of candidates, including EEF1A1, FLNA, ITPRIP, CYP11A1, MT-CO2, GPR175, ACOT2, and QPRT, were further validated in human neuroblastoma cells or brain tissues. Furthermore, our study suggested that NLGN3 was functioning in cytosolic calcium balance and participating in calcium-regulated cellular processes. Our findings of novel NLGN3 binding partners provide evidences of involvement of NLGN3 in multiple biological pathways, especially calcium regulating and mitochondrial function, thus suggesting further significance. This new data not only leads to a better understanding of the physiological functions of NLGN3, but also provide new aspects for pathogenesis of autism.

The cellular and molecular landscape of neuroligins

“…Two independent screens identified many proteins that interact with NLGN2 and NLGN3 c-tails, and these interactions have yet to be characterized [44,54]. Moreover, a critical region was identified in the C-terminal regions of NLGN1 and NLGN3 that is required for these molecules to potentiate excitatory synaptic transmission [24] without a known direct binding partner (Figure 3).…”

Whole exome sequence-based association analyses of plasma amyloid-β in African and European Americans; the Atherosclerosis Risk in Communities-Neurocognitive Study

“…The protein encoded by ITPRIP binds to the inositol-1,4,5-triphosphate receptor (IP 3 R) and allosterically downregulates IP 3 -induced calcium release from the endoplasmic reticulum [54]. Oligomeric aβ 42 alters IP 3 -triggered calcium release [55] and, in return, IP 3 -induced calcium release may influence amyloid precursor protein (APP) cleavage to aβ 40 and aβ 42 [56].…”

“…Oligomeric aβ 42 alters IP 3 -triggered calcium release [55] and, in return, IP 3 -induced calcium release may influence amyloid precursor protein (APP) cleavage to aβ 40 and aβ 42 [56]. Thus, ITPRIP may interact with IP 3 R to modulate both the aβ concentration and synaptic plasticity through calcium signaling [54]. A pathway analysis of plasma aβ GWAS results lent credibility to our ITPRIP finding [12]; eighteen of twenty-seven Ingenuity canonical pathways associated with plasma aβ contained the receptor (IP 3 R) modulated by ITPRIP.…”

Filamin, a synaptic organizer in Drosophila, determines glutamate receptor composition and membrane growth

“…Filamin is present in acetylcholine receptor clusters at the mammalian NMJ (Bloch and Hall, 1983; Shadiack and Nitkin, 1991), but its function there is unknown. In lysates of the mammalian brain, filamin associates with known synaptic proteins such as Shank3, Neuroligin 3, and Kv4.2 (Petrecca et al, 2000; Sakai et al, 2011; Shen et al, 2015). A recent report indicated that filamin degradation promotes a transition from immature filopodia to mature dendritic spines (Segura et al, 2016), a phenomenon that is likely to be related to the actin-bundling properties of the long isoform of filamin.…”