GSK3B Knockout Cell Lysate

ZNRF1 is an E3 ubiquitin ligase constitutively expressed in almost all neurons in the central and peripheral nervous systems during development and in adulthood. From this expression profile, the role of ZNRF1 is assumed to be common to many different types of neurons. We have analyzed the roles of ZNRF1-dependent degradation of target proteins in neurons. In mature neurons, ZNRF1 is activated in response to different types of stress that cause neuronal/axonal degeneration, and degrade AKT to activate GSK3B. Here we summarize the subcellular signaling events downstream of GSK3B activation, and their roles in the progression of neuronal/axonal degeneration. (C) 2018 Elsevier B.V. and Japan Neuroscience Society. All rights reserved.

Tc1 mouse model of Down syndrome (DS) is functionally trisomic for 120 human chromosome 21 (HSA21) classical protein-coding genes. Tc1 mice display features relevant to the DS phenotype, including abnormalities in learning and memory and synaptic plasticity. To determine the molecular basis for the phenotypic features, the levels of 90 phosphorylation-specific and phosphorylation-independent proteins were measured by Reverse Phase Protein Arrays in hippocampus and cortex, and 64 in cerebellum, of Tc1 mice and littermate controls. Abnormal levels of proteins involved in MAP kinase, mTOR, GSK3B and neuregulin signaling were identified in trisomic mice. In addition, altered correlations among the levels of N-methyl-D-aspartate (NMDA) receptor subunits and the HSA21 proteins amyloid beta (A4) precursor protein (APP) and TIAM1, and between immediate early gene (IEG) proteins and the HSA21 protein superoxide dismutase-1 (SOD1) were found in the hippocampus of Tc1 mice, suggesting altered stoichiometry among these sets of functionally interacting proteins. Protein abnormalities in Tc1 mice were compared with the results of a similar analysis of Ts65Dn mice, a DS mouse model that is trisomic for orthologs of 50 genes trisomic in the Tc1 plus an additional 38 HSA21 orthologs. While there are similarities, abnormalities unique to the Tc1 include increased levels of the S100B calcium-binding protein, mTOR proteins RAPTOR and P70S6, the AMP-kinase catalytic subunit AMPKA, the IEG proteins FBJ murine osteosarcoma viral oncogene homolog (CFOS) and activity-regulated cytoskeleton-associated protein (ARC), and the neuregulin 1 receptor ERBB4. These data identify novel perturbations, relevant to neurological function and to some seen in Alzheimers disease, that may occur in the DS brain, potentially contributing to phenotypic features and influencing drug responses.