Project description:Despite extensive investigation of Parkinson's disease (PD), rending oxidative stress, mitochondrial dysfunction, altered proteostasis, and abnormal insulin signaling as potential mechanisms, however, etiology of most cases remains undefined. To reveal the underlying mechanism and determine the correlation of SH2B1 expression and Parkinson’s disease, we monitored the related gene levels during PD progress in humans and mice. For human subjects, we collected plasma from Parkinson’s patients (PD, diagnosed by clinicians and non-PD controls (NC, because brain samples are not available) and performed whole-transcriptome gene expression analysis. The transcriptome microarray enabled detection of the differential expression of 3229 transcripts (FPKM >= 0.1; cutoff of 2.0-fold change; p < 0.05) and further filtering of 952 transcripts (588 up-, 364 down-regulated transcripts in PD; reads > 5, p < 0.05).Based on the unbiased analysis, we revealed that SH2B1, but not SH2B2 or SH2B3, was reduced in PD patients’ plasma. Real-time quantitative polymerase chain reaction (qPCR) confirmed that there was decreased expression of SH2B1 in PD patients’ plasma as well as in plasma from MPTP/p induced murine PD model. SH2B1 is an intracellular adaptor protein that assists signal transduction of several receptor-tyrosine-kinases and elicits beneficial metabolic effects in obesity. Here, we show that SH2B1 is a key component of molecular chaperone autophagy (CMA) that preserves dopaminergic neuron health and counters MPTP/p-induced PD in mice. Sh2b1 deficiency accelerated neuron apoptosis in PD mouse. In contrast, transgenic expression of Sh2b1 in neurons alleviated MPTP/p-induced injury. SH2B1 attenuated neuron apoptosis by binding HSC70 to promote CMA degradation of PLIN4, a lipid droplets (LDs) surrounding protein, thus suppressed PLIN4/LDs mediated lipid peroxidation stress in PD mice brain. Adeno-associated virus–mediated (AAV-mediated) rescue of neuron HSC70 expression in wildtype not Sh2b1-deficent mice functionally restored the neuropathology of PD. Thus, neuronal SH2B1 serves as an assistant in CMA rather than insulin signaling by promoting a CMA substrate degradation to counter MPTP/p-induced neurodegeneration.

Project description:Appetite is frequently affected in cancer patients, leading to anorexia and consequently insufficient food intake. In this study, we report on hypothalamic gene expression profile of a cancer cachectic mouse model with increased food intake. In this model, mice bearing C26 colon adenocarcinoma have an increased food intake subsequently to the loss of body weight. We hypothesize that in this model, appetite regulating systems in the hypothalamus, which apparently fail in anorexia, are still able to adapt adequately to changes in energy balance. Therefore studying the changes that occur on appetite regulators in the hypothalamus might reveal targets for treatment of cancer-induced eating disorders. By applying transcriptomics, many appetite regulating systems in the hypothalamus could be taken into account, providing an overview of changes that occur in the hypothalamus during tumour growth. We show that hypothalamic expression of orexigenic neuropeptides NPY and AgRP was higher, whereas expression of anorexigenic genes CCK and POMC were lower in TB compared to controls. In addition, serotonin and dopamine signalling pathways were found to be significantly altered in TB mice. Serotonin levels in brain showed to be lower in TB mice compared to control mice, while dopamine levels did not change. Moreover, serotonin levels inversely correlated with food intake. Transcriptomic analysis of the hypothalamus of cachectic TB mice with an increased food intake showed changes in NPY, AgRP and serotonin signalling. Serotonin levels in the brain showed to correlate with changes in food intake. Targeting these systems seems a promising strategy to avoid the development of cancer-induced eating disorders. C26-colon adenocarcinoma cells were subcutaneously inoculated in CDF1 mice. After 20 days, hypothalami were dissected and subjected to gene expression profiling. The total dataset consists of 2 parts; dataset 1, a pilot stuy in which mice were injected with increasing number of tumour cells and pooled samples were arrayed; and dataset 2, the main study in which mice were injected with 1 million tumour cells and samples were individually arrayed.

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Deletion of brain-specific isoforms of adapter protein SH2B1 protects mice from obesity in a non-leptin-mediated manner

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