SNX17 Mediates Dendritic Spine Maturation via p140Cap.

Sorting nexin17 (SNX17) is a member of the sorting nexin family, which plays a crucial role in endosomal trafficking. Previous research has shown that SNX17 is involved in the recycling or degradation of various proteins associated with neurodevelopmental and neurological diseases in cell models. However, the significance of SNX17 in neurological function in the mouse brain has not been thoroughly investigated. In this study, we generated Snx17 knockout mice and observed that the homozygous deletion of Snx17 (Snx17-/-) resulted in lethality. On the other hand, heterozygous mutant mice (Snx17+/-) exhibited anxiety-like behavior with a reduced preference for social novelty. Furthermore, Snx17 haploinsufficiency led to impaired synaptic transmission and reduced maturation of dendritic spines. Through GST pulldown and interactome analysis, we identified the SRC kinase inhibitor, p140Cap, as a potential downstream target of SNX17. We also demonstrated that the interaction between p140Cap and SNX17 is crucial for dendritic spine maturation. Together, this study provides the first in vivo evidence highlighting the important role of SNX17 in maintaining neuronal function, as well as regulating social novelty and anxiety-like behaviors.

Ca2+-induced release of IQSEC2/BRAG1 autoinhibition under physiological and pathological conditions.

IQSEC2 (aka BRAG1) is a guanine nucleotide exchange factor (GEF) highly enriched in synapses. As a top neurodevelopmental disorder risk gene, numerous mutations are identified in Iqsec2 in patients with intellectual disabilities accompanied by other developmental, neurological, and psychiatric symptoms, though with poorly understood underlying molecular mechanisms. The atomic structures of IQSECs, together with biochemical analysis, presented in this study reveal an autoinhibition and Ca2+-dependent allosteric activation mechanism for all IQSECs and rationalize how each identified Iqsec2 mutation can alter the structure and function of the enzyme. Transgenic mice modeling two pathogenic variants of Iqsec2 (R359C and Q801P), with one activating and the other inhibiting the GEF activity of the enzyme, recapitulate distinct clinical phenotypes in patients. Our study demonstrates that different mutations on one gene such as Iqsec2 can have distinct neurological phenotypes and accordingly will require different therapeutic strategies.

Sodium-calcium exchanger isoform-3 targeted Withania somnifera (L.) Dunal therapeutic intervention ameliorates cognition in the 5xFAD mouse model of Alzheimer's disease.

The third isoform of the Na+-Ca2+ exchanger (NCX3) is crucial for a physiological fine-tuning of the Ca2+ fluxes in excitable tissues. In this view, the NCX3 accounts for the aberrant Ca2+ influx seen during neuronal excitotoxicity, such as in Alzheimer's disease (AD). However, little is known about NCX3 regulation and functional properties. Withania somnifera (L.) Dunal (W. somnifera), a traditional indigenous plant widely recognized for having numerous medicinal values, was undertaken to determine its potential therapeutic benefit against aggregated Aß1-42-induced NCX3 dysregulation and the thereof cognition impairment in 5xFAD mice. The undertaken sourced dried roots of authenticated W. somnifera physicochemical compositional tests satisfied standards of pharmacognostic quality, and further phytochemical analysis of the roots methanol extract revealed the roots constitute several antioxidants. Following an intra-gastric gavage administration of synthesized W. somnifera roots methanolic extract from postnatal day 30 (P30) to P75, in vivo cognitional studies and then neurochemical examinations of the NCX3 expression level, Aß plaque deposition, and antioxidant activities in the AD-associated brain regions of 4-month-old 5xFAD mice suggests that the oxidative stress normalizing effects of W. somnifera constituents, operating on the NCX3, may have a therapeutic role in the improvement of cognition in AD.

Preparation and characterization of POSS-containing poly(perfluoropolyether)methacrylate hybrid copolymer and its superhydrophobic coating performance.

To design a mechanically stable and superhydrophobic coating, a polyhedral oligomeric silsesquioxane (POSS)-containing poly(perfluoropolyether)methacrylate (PFPEM) hybrid copolymer (PFPEM-POSS) was synthesized via a free-radical solution polymerization with PFPEM, 1H,1H,2H,2H-perfluorooctyl acrylate, methyl (meth)acrylate, n-butyl acrylate, hydroxypropyl acrylate, methacryloxy propyl trimethoxy silane, and methacrylisobutyl POSS; and azobisisobutyronitrile as an initiator. Hydrophobic coatings were formed on substrates by a facile one-step dip-coating method in a solution mixture of diethylene glycol dimethyl ether with the PFPEM-POSS hybrid copolymer. The chemical structure of the PFPEM-POSS copolymer and the surface morphology and performance of the PFPEM-POSS coatings were investigated. The results indicate that, under POSS aggregation via the fluorophilic/oleophilic co-monomer phase separation and owing to the low-surface-energy poly(perfluoropolyether)methacrylate incorporated into the copolymer, PFPEM-POSS exhibited a hierarchical micro-nano roughness in atomic force microscopy observations and provided the treated substrates with excellent hydrophobicity and abrasion resistance. As a result, the water contact angle reached 152.3° on the treated glass.