RNA Sequencing Facilitates Quantitative Analysis of Parkinson's patients (PD) and non-PD control (NC) Plasma Tanscriptomes

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE160299 | GEO | 2023/10/26

REPOSITORIES: GEO