Abstract
Background and Purpose. Alterations in cholesterol homeostasis have been reported in cell and animal models of Parkinson's disease (PD), although there are inconsistent data about the association between serum cholesterol levels and risk of PD. Here, we investigated the effects of miR-873 on lysosomal cholesterol homeostasis and progressive dopaminergic neuron damage in a lipopolysaccharide-(LPS) induced model of PD. Experimental Approach. To evaluate the therapeutic benefit of the miR-873 sponge, rats were injected with a LV-miR-873 sponge or the control vector 3 days before the right-unilateral injection of LPS into the substantia nigra (SN) pars compacta, or 8 and 16 days after LPS injection. Normal SH-SY5Y cells or SH-SY5Y cells overexpressing α-synuclein were used to evaluate the distribution of α-synuclein and cholesterol in lysosomes and to assess the autophagic flux after miR-873 transfection or ABCA1 silencing. The inhibition of miR-873 significantly ameliorated the LPS-induced accumulation of α-synuclein and loss of dopaminergic neurons in the SN at the early stage. miR-873 mediated the inhibition of ABCA1 by LPS. miR-873 transfection or ABCA1 silencing increased the lysosomal cholesterol and α-synuclein levels, and decreased the autophagic flux. The knockdown of ABCA1 or A20, which are the downstream target genes of miR-873, exacerbated the damage to LPS-induced dopaminergic neurons. Conclusion and Implications. The results suggest that the inhibition of miR-873 may play a dual protective role by improving intracellular cholesterol homeostasis and neuroinflammation in PD. The therapeutic effects of the miR-873 sponge in PD may be due to the upregulation of ABCA1 and A20.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disorder, and its pathological changes are characterized by the accumulation of α-synuclein within Lewy bodies and the loss of dopamine (DA) neurons in the substantia nigra (SN)
More recent data suggest that the main mechanism of α-synuclein clearance is lysosome-dependent autophagy, multiple mechanisms are involved in the degradation of α-synuclein including the ubiquitin proteasome pathway [1]
On day 22 after LPS treatment, the DA neurons on the lesioned SN side were reduced by 55.5% (p < 0:001) compared with those on the intact side; the DA neurons were decreased by 22.8% (p < 0:001) in the rats injected with the miR-873 sponge 3 days before LPS treatment, and by 32.8% (p < 0:01) in the rats injected with the miR-873 sponge 8 days after LPS treatment (Figures 1(b) and 1(c))
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disorder, and its pathological changes are characterized by the accumulation of α-synuclein within Lewy bodies and the loss of dopamine (DA) neurons in the substantia nigra (SN). Alterations in cholesterol homeostasis have been reported in cell or animal models of PD, there are inconsistent data about the association between serum cholesterol levels and risk of PD [3]. Alterations in cholesterol homeostasis have been reported in cell and animal models of Parkinson’s disease (PD), there are inconsistent data about the association between serum cholesterol levels and risk of PD. We investigated the effects of miR-873 on lysosomal cholesterol homeostasis and progressive dopaminergic neuron damage in a lipopolysaccharide-(LPS) induced model of PD. Normal SH-SY5Y cells or SH-SY5Y cells overexpressing α-synuclein were used to evaluate the distribution of α-synuclein and cholesterol in lysosomes and to assess the autophagic flux after miR-873 transfection or ABCA1 silencing. MiR-873 transfection or ABCA1 silencing increased the lysosomal cholesterol and α-synuclein levels, and decreased the autophagic flux. The therapeutic effects of the miR-873 sponge in PD may be due to the upregulation of ABCA1 and A20
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