Harnessing the trophic and modulatory potential of statins in a dopaminergic cell line

Abstract

The identification of an effective disease-modifying treatment for the neurodegenerative progression in Parkinson's disease (PD) remains a major challenge. Epidemiological studies have reported that intake of statins, cholesterol lowering drugs, could be associated to a reduced risk of developing PD. In-vivo studies suggest that statins may reduce the severity of dopaminergic neurodegeneration. The trophic potential of statins and their impact on the expression of dopaminergic synaptic markers and dopamine (DA) transport function in SH-SY5Y cells has been investigated. The findings showed that statin treatment induces neurite outgrowth involving a specific effect on the complexity of the neurite branching pattern. Statins increased the levels of presynaptic dopaminergic biomarkers such as vesicular monoamine transporter 2 (VMAT2), synaptic vesicle glycoproteins 2A and 2C (SV2C), and synaptogyrin-3 (SYNGR3). Gene expression analysis confirmed a rapid statin-induced up-regulation of VMAT2-, SV2C-, and SYNGR3-mRNA levels. Assessment of [(3) H]DA transport in statin-treated cells showed a reduction in DA uptake concomitant to a modification of VMAT2 pharmacological properties. It was also observed that a nuclear translocation of the sterol regulatory element-binding protein 1 (SREBP-1). The results suggested that statins induced phenotypic changes in dopaminergic cells characterized by an increase of growth, complexity of structural synaptic elements, and expression of key presynaptic proteins with functional impact on the DA transport capacity. Statin-induced changes are likely the result of a downstream modulation of SREBP-1 pathway. Overall, these mechanisms may contribute to the neuroprotective or neurorestorative effects observed in the dopaminergic system and strengthen the therapeutic potential of statins for PD.

U18666A, an activator of sterol regulatory element binding protein pathway, modulates presynaptic dopaminergic phenotype of SH-SY5Y neuroblastoma cells

“…The effects of pharmacological treatments with U18666A and PF‐429242 on SREBP‐1 nuclear translocation and protein expression were analyzed by immunofluorescence using antibodies against the synaptic markers and SREBP‐1. The immunocytochemistry protocol and high‐content image analysis were previously described (Schmitt et al, ). Briefly, following the treatment, cells were washed with phosphate‐buffered saline (PBS) followed by fixation with 4% paraformaldehyde for 30 min (room temperature) and permeabilization (triton X‐100 0.05%, 10 min).…”

“…The qRT‐PCR protocol was performed as previously described (Schmitt et al, ). After a time‐course pharmacologic treatment (6, 12, 24, and 48 hr) with SREBP modulators and combination treatments between SREBP modulators and lovastatin, the total SH‐SY5Y cellular RNA was isolated using the RNeasy mini kit (Qiagen, Venlo, Netherlands) according to the manufacturer's protocol.…”

“…Very recently, we have demonstrated that statins, concomitantly to their trophic effects, also induced upregulation of presynaptic dopaminergic markers in neuroblastoma cells (Schmitt et al, ). Treatment with statins consistently increased the expression of vesicular monoamine transporter 2 (VMAT2), synaptogyrin‐3 (SYNGR3), and synaptic vesicles glycoprotein 2 C (SV2C) (Schmitt et al, ) which are key players for the regulation of the presynaptic vesicular dopamine system (Bernstein, Stout, & Miller, ; Dardou et al, ; Egana et al, ). Our findings showed that both trophic effects and phenotypic changes were accompanied by nuclear translocation of the transcription factor sterol regulatory element‐binding proteins (SREBP) (Schmitt et al, ).…”

“…Statins have been shown to protect neuronal cells against the neurotoxic effects of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) (Castro et al, ; Ghosh et al, ) and 6‐hydroxydopamine (Xu et al, ; Yan et al, ). It has been suggested that statin‐induced protection may be mediated by diverse mechanisms such as their inhibitory action on proinflammatory processes, oxidative stress, and α‐synuclein aggregation (Ghosh et al, ; Kumar, Sharma, Gupta, Kalonia, & Mishra, ; Roy and Pahan, ; Xu et al, ) or by their neurotrophic effects (Evangelopoulos, Weis, & Kruttgen, ; Jin et al, ; Lu et al, ; Pooler, Xi, & Wurtman, ; Raina, Gupta, Yadav, & Surolia, ; Robin et al, ; Sato‐Suzuki and Murota, ; Schmitt, Dehay, Bezard, & Garcia‐Ladona, ; Schulz et al, ; Watanabe et al, ). Statins have been shown to modulate different pathways downstream to 3‐hydroxy‐3‐methylglutaryl‐coenzyme A (HGM‐CoA) inhibition.…”

“…Treatment with statins consistently increased the expression of vesicular monoamine transporter 2 (VMAT2), synaptogyrin‐3 (SYNGR3), and synaptic vesicles glycoprotein 2 C (SV2C) (Schmitt et al, ) which are key players for the regulation of the presynaptic vesicular dopamine system (Bernstein, Stout, & Miller, ; Dardou et al, ; Egana et al, ). Our findings showed that both trophic effects and phenotypic changes were accompanied by nuclear translocation of the transcription factor sterol regulatory element‐binding proteins (SREBP) (Schmitt et al, ). These data clearly suggested an important role of this transcription pathway in the modulation of dopaminergic phenotype and the neurite growth induced by statins.…”