Loss of sorting nexin 27 contributes to excitatory synaptic dysfunction by modulating glutamate receptor recycling in Down's syndrome

Abstract

Sorting nexin 27 (SNX27), a brain-enriched PDZ domain protein, regulates endocytic sorting and trafficking. Here, we show that Snx27−/− mice exhibit severe neuronal deficits in the hippocampus and cortex. While Snx27+/− mice exhibit grossly normal neuroanatomy, we find defects in synaptic function, learning and memory, and a reduction in ionotropic glutamate receptors (NMDARs and AMPARs). SNX27 interacts with these receptors through its PDZ domain, regulating their recycling to the plasma membrane. We demonstrate a concomitant reduction of SNX27 and C/EBPβ in Down syndrome brains and identify C/EBPβ as a transcription factor for SNX27. Down syndrome causes over-expression of miR-155, a chromosome 21-encoded microRNA that negatively regulates C/EBPβ, thereby reducing SNX27 and resulting in synaptic dysfunction. Up-regulating SNX27 in the hippocampus of Down syndrome mice rescues synaptic and cognitive deficits. Our identification of the role of SNX27 in synaptic function establishes a novel molecular mechanism of Down syndrome pathogenesis.

The Use of Pharmacological Retromer Chaperones in Alzheimer's Disease and other Endosomal-related Disorders

“…Retromer-related dysfunctions have been reported not only in neurological disorders such as Down syndrome [29,30], hereditary spastic paraplegia [31], cerebral lipofuscinosis [32], prionopathy [33], and Nieman Pick type C1 disease [34], but have also been linked to non-neurological disorders such as type II diabetes [35,36], osteoporosis [37], retinal degeneration [38], and Legionella disease [39] (see Table 1). Several of these diseases have a clear pathological molecular link to retromer; in other cases, the connection is less clear and more tangential.…”

VPS26A–SNX27 Interaction-Dependent mGluR5 Recycling in Dorsal Horn Neurons Mediates Neuropathic Pain in Rats

“…Retromer, a stable trimer composed of vacuolar protein sorting-associated protein 26 (VPS26), VPS29, and VPS35 (Collins et al, 2005;Hierro et al, 2007;Gallon et al, 2015), has been identified as a critical element of the endosomal sorting machinery that initiates cargo sorting for re-trieval and recycling to the plasma membrane or trans-Golgi network and therefore away from degradation . Mammalian-retromer-dependent recycling of the signaling receptor is associated with glutamatergic receptor-dependent neural plasticity at excitatory synapses in multiple neuropathologies, such as Alzheimer's disease (Wen et al, 2011) and Down's syndrome (Wang et al, 2013). However, the potential contribution of retromer-dependent cycling in spinal glutamate-receptor-associated pain hypersensitivity has not been established.…”

A role for novel lipid interactions in the dynamic recruitment of SNX27 to the T-cell immune synapse

“…SNX27 is proving to be a critical recycling protein in the nervous system, and its down-regulation is associated with pathological conditions characteristic of Alzheimer disease or Down syndrome. 2,38 A comprehensive study of SNX27 function at the IS, including PDZ-binding cargos, may thus help elucidate the role of SNX27 in the immune and other cellular systems.…”

“…Proteins with a PDZ domain are often found in the postsynaptic density of neuronal synapses, where SNX27 participates specifically in glutamate and b-adrenoreceptor trafficking. [1][2][3] In other polarized models such as activated T cells, the PDZ domain mediates SNX27 interaction with diacylglycerol kinase zeta (DGKz), a negative regulator of T cell activation that attenuates diacylglycerol (DAG)-mediated signals by catalyzing DAG conversion into phosphatidic acid (PA). 4 In addition, SNX27 binds ubiquitously expressed transmembrane cargos such as glucose and metal ion transporters that have a class I PDZ binding motif (PDZ-bm).…”