The Role Of DEC1/LXRβ In Parkinson’s Disease

BACKGROUND: Parkinson’s disease(PD) is a progressive neurodegenerative disease, which is characterized by extensive dopamine neuron degeneration in the substantia nigra pars compacta(SNpc). DEC1(BHLHB2/Stra13/Sharp2)-a basic helix-loop-helix transcription factor-is known to be involved in various biological phenomena, such as neurogenesis. Live X receptor β(LXRβ) is a member of the nuclear receptor super gene family expressed in the central nervous system, where is important for cortical layering during development and survival of dopaminergic neurons throughout life.AIM: To investigate the roles of DEC1 in the progression of PDMETHODS: 1. Comparisons were carried out between wide-type mice and PD models, induced by MPTP administration in wide-type mice, and DEC1-/- mice were also included. 2. Dopaminergic neurons and the expression of LXRβ were detected by immunohistochemistry in wide-type mice and DEC1-/- mice.Changes in the levels of DEC1 and LXRβ expressed on Dopaminergic neurons in PD model mice were also measured. 3. The levels of DEC1, LXRβ and the target genes(ABCG1, ABCG5, ABCG8) were detected by Western blot in vitro model of Parkinson’s disease, SH-SY5 Y cells treated with two concentrations of the neurotoxin 1-methyl-4-phenylpyridinium ion(MPP+). 4. The protein levels of these genes were also measured when DEC1 was overexpressed and then treated with MPP+ in SH-SY5 Y cells. 5. Inhibition and apoptosis of SH-SY5 Y caused by MPP+ were determined by Sulforhodamine B(SRB) assay and Hoechst staining, respectively. Moreover, the cases when DEC1 was overexressed were also detected. 6. The protein levels of DEC1 and LXRβ in midbrain of PD mice models, treated with MPTP, were detected by Western blot. 7. The protein levels of DEC1 and LXRβwere also detected in primary cultured astrocytes with the treatment of MPP+ in two concentrations.RESULTS: 1. We could detect the expressions of Stra13 and LXRβ in dopamnergic neurons in midbrain in wide-type mice;2. Immunohistochemistry results showed that the number of dopamnergic neurons in midbrain of PD modle mice was lost compared with the controls, and, correspondingly, the levels of Stra13 and LXRβ in this area were decreased; however, Western blot results showed that the expressions of Stra13 and LXRβ were obviously increased;3. Compared with wide-type mice, the number of dopaminergic neurons and the level of LXRβ in dopaminergic neurons were decreased in DEC1-/- mice;4. In vitro, SH-SY5 Y cells treated with the neurotoxin 1-methyl-4-phenylpyridinium ion(MPP+), DEC1 decreased in a dosage-dependent manner. The level of DEC1 could drop to the half when the concentration of MPP+ was up to 100μM, compared with the control. Moreover, MPP+ compressed the expressions of LXRβ and the target genes(ABCG1, ABCG5, ABCG8) in a dosage-dependent manner, too. These results were consistent with the results in vivo.5. Overexpression of DEC1 not only increased the expression of LXRβ, as well as the target genes, but also attenuated the decreased protein levels caused by MPP+. With the treatment of MPP+, SH-SY5 Y showed abnormal cell growth with significant reductions in the cell vitality and significant increases in the apoptotic rate. The inhibition ratio was up to almost 40%(P<0.001) when the strength was 400μM. However, overexpression of DEC1 could also attenuate the damage caused by MPP+. In detail, the inhibition ratio was just around a quarter(P<0.01) in the same concentration of MPP+.6. Primary cultured astrocytes expressed Stra13 and MPP+ induced expression ofStra13 in a dosage-dependent manner. In detail, when astrocytes were treated with MPP+ in the concentration of 100μM, the expression of Stra13 was about twice(P<0.001) as much as that of control. In addition, the expression of LXRβ was also increased. These results strongly support that the overall increased Stra13 induced by MPTP in the midbrain tissue is due to the increased Stra13 expression in astrocyte cells.CONCLUSIONS: The responses of dopaminergic neurons and astrocytes to MPP+ or MPTP were differential, in terms of the expression of DEC1. DEC1(Stra13) could regulate LXRβ and the targets genes in the central nervous system(CNS). DEC1 may play a role in the progression of PD. The mechanism will to be determined.