Sorting nexin 27 (<i>SNX27</i>) variants associated with seizures, developmental delay, behavioral disturbance, and subcortical brain abnormalities

Parente, Daniel J.; Morris, Stephanie; McKinstry, Robert C.; Brandt, Tracy; Gabau, Elisabeth; Ruiz, Anna; Shinawi, Marwan

doi:10.1111/cge.13675

Cited by 11 publications

(14 citation statements)

References 41 publications

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“…Patients lacking SNX27 expression or expressing predicted damaging inherited SNX27 variants display a range of neuronal phenotypes that include developmental delays, abnormal neurocognitive function, epilepsy, various types of seizure, and subcortical white matter abnormalities (16,17). While known SNX27-associated neuronal integral proteins, such as NMDA receptors (26,39), 5-HT4 receptor (4), metabotropic glutamate receptor 5 (mGluR5) (45), neuroligin 2 (44,46), and Kir3 channels (27), have provided some insight into these complex phenotypes our unbiased quantitative identification of the neuronal SNX27 interactome has revealed an additional cohort of integral neuronal proteins that associate with SNX27.…”

Section: Discussionmentioning

confidence: 99%

“…With the notable exception of defects in the CCC complex mediated retrieval and recycling of low-density lipoprotein (LDL) receptor and the clearance of circulating LDL-cholesterol during hypercholesterolaemia and atherosclerosis (14,15), how defects in the cell surface proteome, that arise from perturbed endosomal sorting, relate to the aetiology of these complex disorders remains poorly understood. A case in point is sorting nexin-27 (SNX27), in which destabilised expression is associated with Down's Syndrome and coding mutations are observed in patients with pleomorphic phenotypes that have at their core epilepsy, developmental delay and subcortical white matter abnormalities (16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

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Sorting nexin-27 regulates AMPA receptor trafficking through the synaptic adhesion protein LRFN2

McMillan

Banks

Hellel

et al. 2020

Preprint

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The endosome-associated cargo adaptor sorting nexin-27 (SNX27) is linked to various neuropathologies through sorting of integral proteins to the synaptic surface, most notably AMPA receptors. To provide a broader view of SNX27associated pathologies we have performed unbiased proteomics to identify new neuronal SNX27-dependent cargoes, and identified proteins linked to excitotoxicity (SLC1A3, SLC4A7, SLC6A11), epilepsy, intellectual disabilities and working memory deficits (KCNT2, ADAM22, KIDINS220, LRFN2).Focusing on the synaptic adhesion molecule leucine-rich repeat and fibronectin type-III domain-containing protein 2 (LRFN2), we establish that SNX27 binds to LRFN2 and is responsible for regulating its endosomal sorting. LRFN2 associates with AMPA receptors and knockdown of LRFN2 phenocopies SNX27 depletion in decreasing surface expression of AMPA receptors, reducing synaptic activity and attenuating hippocampal long-term potentiation.Our evidence suggests that, in contrast to previous reports, SNX27 does not directly bind to AMPA receptors, and instead controls AMPA receptor-mediated synaptic transmission and plasticity indirectly through the endosomal sorting of LRFN2. Overall, our study provides new molecular insight into the perturbed function of SNX27 and LRFN2 in a range of neurological conditions.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Sorting nexin-27 regulates AMPA receptor trafficking through the synaptic adhesion protein LRFN2

McMillan

Banks

Hellel

et al. 2020

Preprint

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“…In neuronal cells, the composition of the cellular membrane is essential for responding to extracellular stimuli and neuroplasticity. SNX-mediated regulation of the cellular membrane composition influences several processes such as neuronal excitability, plasticity, neural development, signaling, psychostimulant response, and cellular drug resistance [184].…”

Section: The Role Of Sorting Nexins In Neurogenerative Diseasesmentioning

confidence: 99%

“…SNX deficiencies have been implemented in Down's syndrome [67] as well as associated with epilepsy, developmental delays, and subcortical brain abnormalities [184].…”

Section: The Role Of Sorting Nexins In Neurogenerative Diseasesmentioning

confidence: 99%

“…variants exhibit a wide range of neurological aberrations that may be associated with defects in cell surface receptors [68].Some of these receptors include neuroreceptors (AMPA, NMDA), ATPase copper transporters, glucose transporters, disintegrin /metalloproteinase, and adhesion proteins (NLGN2) [184]. [198].In the field of virology, viral entry has been extensively studied for its promising impacts in future therapeutic strategies.…”

Section: The Role Of Sorting Nexins In Neurogenerative Diseasesmentioning

confidence: 99%

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Sorting Nexins in Protein Homeostasis

Hanley¹,

Cooper²

2020

Preprint

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Sorting nexins (SNXs) are a highly conserved membrane-associated protein family that plays a role in regulating protein homeostasis. This family of proteins is unified by their characteristic phox (PX) phosphoinositides binding domain. Along with binding to membranes, this family of SNXs also comprises a diverse array of protein-protein interaction motifs that are required for cellular sorting and protein trafficking. SNXs play a role in maintaining the integrity of the proteome which is essential for regulating multiple fundamental processes such as cell cycle progression, transcription, metabolism, and stress response. To tightly regulate these processes proteins must be expressed and degraded in the correct location and at the correct time. The cell employs several proteolysis mechanisms to ensure that proteins are selectively degraded at the appropriate spatiotemporal conditions. SNXs play a role in ubiquitin-mediated protein homeostasis at multiple levels including cargo localization, recycling, degradation, and function. In this review, we will discuss the role of SNXs in three different protein homeostasis systems: endocytosis lysosomal, the ubiquitin-proteasomal, and the autophagy-lysosomal system. The highly conserved nature of this protein family by beginning with the early research on SNXs and protein trafficking in yeast and lead into their important roles in mammalian systems. Underlying the importance of SNXs in protein homeostasis, genetic defects in SNXs have been linked with a variety of human diseases such as cancer, cardiovascular disease, neurogenerative disease, and viral infections.

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Sorting Out Sorting Nexins Functions in the Nervous System in Health and Disease

et al. 2021

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Endocytosis is a fundamental process that controls protein/lipid composition of the plasma membrane, thereby shaping cellular metabolism, sensing, adhesion, signaling, and nutrient uptake. Endocytosis is essential for the cell to adapt to its surrounding environment, and a tight regulation of the endocytic mechanisms is required to maintain cell function and survival. This is particularly significant in the central nervous system (CNS), where composition of neuronal cell surface is crucial for synaptic functioning. In fact, distinct pathologies of the CNS are tightly linked to abnormal endolysosomal function, and several genome wide association analysis (GWAS) and biochemical studies have identified intracellular trafficking regulators as genetic risk factors for such pathologies. The sorting nexins (SNXs) are a family of proteins involved in protein trafficking regulation and signaling. SNXs dysregulation occurs in patients with Alzheimer’s disease (AD), Down’s syndrome (DS), schizophrenia, ataxia and epilepsy, among others, establishing clear roles for this protein family in pathology. Interestingly, restoration of SNXs levels has been shown to trigger synaptic plasticity recovery in a DS mouse model. This review encompasses an historical and evolutionary overview of SNXs protein family, focusing on its organization, phyla conservation, and evolution throughout the development of the nervous system during speciation. We will also survey SNXs molecular interactions and highlight how defects on SNXs underlie distinct pathologies of the CNS. Ultimately, we discuss possible strategies of intervention, surveying how our knowledge about the fundamental processes regulated by SNXs can be applied to the identification of novel therapeutic avenues for SNXs-related disorders.

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Sorting nexin 27 (SNX27) variants associated with seizures, developmental delay, behavioral disturbance, and subcortical brain abnormalities

Cited by 11 publications

References 41 publications

Sorting nexin-27 regulates AMPA receptor trafficking through the synaptic adhesion protein LRFN2

Sorting nexin-27 regulates AMPA receptor trafficking through the synaptic adhesion protein LRFN2

Sorting Nexins in Protein Homeostasis

Sorting Out Sorting Nexins Functions in the Nervous System in Health and Disease

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