Iron deposition is present in main lesion areas in the brains of patients with Parkinson’s disease (PD) and an abnormal iron content may be associated with dopaminergic neuronal cytotoxicity and degeneration in the substantia nigra of the midbrain. However, the cause of iron deposition and its role in the pathological process of PD are unclear. In the present study, we investigated the effects of the nasal mucosal delivery of synthetic human α-synuclein (α-syn) preformed fibrils (PFFs) on the pathogenesis of PD in Macaca fascicularis. We detected that iron deposition was clearly increased in a time-dependent manner from 1 to 17 months in the substantia nigra and globus pallidus, highly contrasting to other brain regions after treatments with α-syn PFFs. At the cellular level, the iron deposits were specifically localized in microglia but not in dopaminergic neurons, nor in other types of glial cells in the substantia nigra, whereas the expression of transferrin (TF), TF receptor 1 (TFR1), TF receptor 2 (TFR2), and ferroportin (FPn) was increased in dopaminergic neurons. Furthermore, no clear dopaminergic neuron loss was observed in the substantia nigra, but with decreased immunoreactivity of tyrosine hydroxylase (TH) and appearance of axonal swelling in the putamen. The brain region-enriched and cell-type-dependent iron localizations indicate that the intranasal α-syn PFFs treatment-induced iron depositions in microglia in the substantia nigra may appear as an early cellular response that may initiate neuroinflammation in the dopaminergic system before cell death occurs. Our data suggest that the inhibition of iron deposition may be a potential approach for the early prevention and treatment of PD.

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To study the effects and mechanisms of Tanshinone IIA (Tan IIA) on the dihydrotestosterone (DHT)-induced expression of sterol regulatory element binding protein-1 (SREBP-1), the synthesis and secretion of lipids in HaCaT cells were examined. HaCaT cells were treated with DHT and Tan IIA at different concentrations. Real-time PCR was used to detect the expression of SREBP-1c, fatty acid synthase (FAS), acyl-CoA synthetase (ACS), stearoyl-CoA desaturase (SCD) and HMG-CoA reductase (HMGCR) mRNA in HaCaT cells. Western blotting was used to analyze the protein expression of SREBP-1 and phosphorylation of Akt. Flow cytometry and Nile red staining were used to detect the synthesis and secretion of lipids in HaCaT cells. We observed that Tan IIA inhibited the DHT-induced expression of SREBP-1 and p-AKT in HaCaT cells, which produced an effect similar to that of LY294002. Tan IIA significantly inhibited the transcription of lipid synthesis-related genes and decreased lipid secretion in HaCaT cells. In conclusion, Tan IIA downregulates the expression of lipid synthesis-related genes and decreases lipid secretion in HaCaT cells, which is correlated with the inhibitory effect on the DHT-induced mRNA and protein expression of SREBP-1 in HaCaT cells.

Background Parkinson’s disease (PD) is mainly characterized by the pathological feature of α-synuclein (α-syn) aggregation, with the exact disease pathogenesis unclear. During the onset and progression of PD, synaptic dysfunction including dysregulation of axonal transport, impaired exocytosis and endocytosis are identified as crucial events of PD pathogenesis. It has been reported that overexpression of α-syn impairs clathrin-mediated endocytosis (CME) in the synapses. However, the underlying mechanisms remained unknown. Methods In this study, we investigated the molecular events underlying the synaptic dysfunction induced by overexpression of wild-type human α-syn and its mutant form, involving series of proteins participating in CME. Results We found that excessive human α-syn causes impaired fission and uncoating of clathrin-coated vesicles (CCVs) during synaptic vesicle recycling, leading to reduced clustering of synaptic vesicles near the active zone and increased size of plasma membrane and number of endocytic intermediates. Furthermore, overexpressed human α-syn induced changes of CME associated proteins, among which synaptojanin1 (SYNJ1) showed significant reduction in various brain regions. Overexpression of SYNJ1 in the primary neuron of α-syn transgenic mice recovered the synaptic vesicle density and clustering. Using fluorescence-conjugated transferrin, we demonstrated that SYNJ1 re-boosted the CME activity by restoring the phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] homeostasis. Conclusions In summary, our data suggested that overexpression of α-syn disrupts synaptic function through interfering with vesicle recycling, which could be alleviated by re-availing of SYNJ1. Our study unrevealed a molecular mechanism of the synaptic dysfunction in PD pathogenesis and provided a potential therapeutic target for treating PD.