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Joubert syndrome is an autosomal recessive disorder characterized by congenital malformation of the cerebellum and brainstem, with abnormal decussation in the brain. Mutations in the Abelson helper integration site 1 gene, which encodes the protein AHI1, have been shown to cause Joubert syndrome. In this study, we found that mouse Ahi1 formed a stable complex with huntingtin-associated protein 1 (Hap1), which is critical for neonatal development and involved in intracellular trafficking. Hap1-knockout mice showed significantly reduced Ahi1 levels, defective cerebellar development, and abnormal axonal decussation. Suppression of Ahi1 also decreased the level of Hap1; and truncated Ahi1, which corresponds to the mutations in Joubert syndrome, inhibited neurite outgrowth in neuronal culture. Reducing Hap1 expression suppressed the level and internalization of TrkB, a neurotrophic factor receptor that mediates neurogenesis and neuronal differentiation, which led to decreased TrkB signaling. These findings provide insight into the pathogenesis of Joubert syndrome and demonstrate the critical role of the Ahi1-Hap1 complex in early brain development., Introduction Clinical features of Joubert syndrome (JS) include neonatal hypotonia (loss of muscle tone), ataxia, developmental delay, mental retardation, and frequently abnormalities in breathing and eye movements (1-3). Various abnormalities [...]

The hypothalamus responds to circulating leptin and insulin in the control of food intake and body weight. A number of neurotransmitters in the hypothalamus, including [gamma]-aminobutyric acid (GABA), also have key roles in feeding. Huntingtin-associated protein 1 (Hap1) is expressed more abundantly in the hypothalamus than in other brain regions, and lack of Hap1 in mice leads to early postnatal death. Hap1 is also involved in intracellular trafficking of the GABA[sub.A] receptor. Here, we report that fasting upregulates the expression of Hap1 in the rodent hypothalamus, whereas intracerebroventricular administration of insulin downregulates Hap1 by increasing its degradation through ubiquitination. Decreasing the expression of mouse hypothalamic Hap1 by siRNA reduces the level and activity of hypothalamic GABA[sub.A] receptors and causes a decrease in food intake and body weight. These findings provide evidence linking hypothalamic Hap1 to GABA in the stimulation of feeding and suggest that this mechanism is involved in the feeding-inhibitory actions of insulin in the brain., Author(s): Guoqing Sheng [1]; Guo-qing Chang [2]; John Y Lin [3]; Zhao-Xue Yu [1]; Zhi-Hui Fang [1]; Juan Rong [1]; Stuart A Lipton [3, 4]; Shi-Hua Li [1]; Gang Tong [...]

Ge-Doped Li0.33La0.56TiO3 (Ge-LLTO) perovskites are synthesized with various GeO2 contents by solid-state reactions as Li-ion conductive electrolytes for rechargeable all-solid-state Li batteries. After the addition of GeO2, the sinterability and Li ion conductivity are enhanced for the perovskite solid electrolyte. The Li0.43La0.56Ti0.95Ge0.05O3 electrolytes exhibit the highest sinterability and Li ion conductivity among the as-prepared Li0.33+2xLa0.56Ti1−xGexO3 electrolytes. The improvement of Li ion conductivity might be attributed to the improvement of the densification and structural integrity of the LLTO solid electrolyte. The lithium transference number (tLi+) of Ge-doped LLTO is close to 1. Moreover, the Ge-LLTO electrolytes are stable in the potential range of 0–10 V vs. Li/Li+. [ABSTRACT FROM AUTHOR]

Joubert syndrome is an autosomal recessive disorder characterized by congenital malformation of the cerebellum and brainstem, with abnormal decussation in the brain. Mutations in the Abelson helper integration site 1 gene, which encodes the protein AHI1, have been shown to cause Joubert syndrome. In this study, we found that mouse Ahi1 formed a stable complex with huntingtin-associated protein 1 (Hap1), which is critical for neonatal development and involved in intracellular trafficking. Hap1-knockout mice showed significantly reduced Ahi1 levels, defective cerebellar development, and abnormal axonal decussation. Suppression of Ahi1 also decreased the level of Hap1; and truncated Ahi1, which corresponds to the mutations in Joubert syndrome, inhibited neurite outgrowth in neuronal culture. Reducing Hap1 expression suppressed the level and internalization of TrkB, a neurotrophic factor receptor that mediates neurogenesis and neuronal differentiation, which led to decreased TrkB signaling. These findings provide insight into the pathogenesis of Joubert syndrome and demonstrate the critical role of the Ahi1-Hap1 complex in early brain development. [ABSTRACT FROM AUTHOR]

Flowerlike NiCo 2 S 4 hollow sub-microspheres are synthesized through Cu 2 O templates to support Pd nanoparticles as high-efficiency catalysts for the hydrogen evolution reaction (HER). The diameter and shell size of NiCo 2 S 4 hollow sub-microspheres are about 400 and 16 nm, respectively. In addition, the surface of the shells is constructed by petallike nanosheets. About 3 nm Pd particles uniformly incorporate with the flowerlike NiCo 2 S 4 hollow sub-microsphere to form the NiCo 2 S 4 /Pd heterostructure. The NiCo 2 S 4 /Pd catalysts exhibit significantly lower overpotential of only 87 and 83 mV at 10 mA/cm 2 for the HER in both acidic and alkaline conditions, respectively, relative to NiCo 2 S 4 (247, 226 mV) and Pd (175, 385 mV) catalysts. Besides, the NiCo 2 S 4 /Pd catalysts also exhibit excellent stability of HER in these two conditions. The superior HER performance of NiCo 2 S 4 /Pd might be resulted from the unique architecture of metal nanoparticles anchored on the bimetallic sulfide flowerlike hollow sub-microspheres, which could provide high surface area, lots of active sites, strong synergetic effect, and stable structure.

Mutant huntingtin can affect vesicular and receptor trafficking via its abnormal protein interactions, suggesting that impairment of intracellular trafficking may contribute to Huntington's disease. There is growing evidence that huntingtin-associated protein-1 (HAP1) also interacts with microtubule-dependent transporters and is involved in intracellular trafficking. However, it remains unclear how the trafficking of HAP1 is regulated and contributes to neuronal function. Here we report that phosphorylation of HAP1 decreases its association with microtubule-dependent transport proteins dynactin p150 and kinesin light chain and reduces its localization in neurite tips. Suppressing HAP1 expression by RNA interference reduces neurite outgrowth and the level of tropomyosin-related kinase A receptor tyrosine kinase (TrkA), a nerve growth factor receptor whose internalization and trafficking are required for neurite outgrowth. HAP1 maintains the normal level of membrane TrkA by preventing the degradation of internalized TrkA. Mutant huntingtin also reduces the association of HAP1 with dynactin p150 and kinesin light chain and thereby decreases the intracellular level of TrkA. These findings suggest that HAP1 trafficking is critical for the stability of TrkA and neurite function, both of which can be attenuated by mutant huntingtin.