Sigma-1 receptor (Sig-1R) functions as a chaperon that interacts with multiple proteins and lipids and is implicated in neurodegenerative and psychiatric diseases. This year in a collaboration with Dr. Bonci's lab we found that vesicular glutamate transporters in dopamine neurons play a critical role in neuroprotection against MPTP-induced Parkinsonism in a rat model. Specifically, genetic deletion of the vesicular glutamate transporter enhances the neurotoxicity of MPTP. Although the sigma-1 receptor was not examined in this study, we feel that the result of this study may have a bearing with the sigma-1 receptor because the sigma-1 receptor has been shown to protect against Parkinsonism. In another study on neuroprotection, we found that Sp1 was highly expressed in astrocytes, implying that Sp1 might be important for the function of astrocytes. Sp1/GFAP-Cre-ERT2 conditional knockout mice were constructed to study the role of Sp1 in astrocytes. Knockout of Sp1 in astrocytes altered astrocytic morphology and decreased GFAP expression in the cortex and hippocampus but did not affect cell viability. Loss of Sp1 in astrocytes decreased the number of neurons in the cortex and hippocampus. Conditioned medium from primary astrocytes with Sp1 knockout disrupted neuronal dendritic outgrowth and synapse formation, resulting in abnormal learning, memory, and motor behavior. Sp1 knockout in astrocytes altered gene expression, including decreasing the expression of Toll-like receptor 2 and Cfb and increasing the expression of C1q and C4Bp, thereby affecting neurite outgrowth and synapse formation, resulting in disordered neuron function. Studying these gene regulations might be beneficial to understanding neuronal development and brain injury prevention. Since the sigma-1 receptor can affect chromatin remodeling via an interaction with the nuclear envelope protein, future investigation on the potential interaction of sigma-1 receptor and Sp1 may advance our understanding on the transcriptional regulation of sigma-1 receptor.
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