Inhibition of transcription factor SP1 produces neuroprotective effects through decreasing MAO B activity in MPTP/MPP⁺ Parkinson's disease models

Abstract

Monoamine oxidase B (MAO B) inhibitors, which inhibit dopamine decomposition by antagonizing MAO B activity, are approved and widely used for clinical treatment of Parkinson's disease (PD). Nonetheless, the mechanism of the abnormally increased MAO B activity in PD is still unclear. Previous research showed transcription factor specificity protein 1 (SP1) directly regulates MAO B activity by binding the SP1 binding sequence in MAO B promoter. In our study, we first observed that the SP1 protein level and SP1 binding activity in the MAO B promoter were increased in 1-methyl-4-phenylpyridinium (MPP ) neurotoxin-induced SH-SY5Y cells. Inhibition of SP1 by pretreatment with SP1 inhibitor mithramycin A (MMA) attenuated the abnormal increase in SP1 binding activity and the MAO B protein level to basal levels. Then, we investigated the neuroprotective effects of SP1 inhibition. In SH-SY5Y cell models of PD, preincubation with MMA or knockdown by SP1-specific small interfering RNA showed potent protection against MPP -induced apoptosis via SP1. In a male C57BL/6 mouse model of PD, MAO B activity and MPP concentrations in mouse brain following injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were increased, whereas the elevated MAO B activity was decreased after pre-injection of MMA. Moreover, MMA ameliorated MPTP-induced loss of dopaminergic neurons in the substantia nigra pars compacta and mouse behavioral impairments. Altogether, our study suggests that SP1 is a principal factor regulating increases in MAO B activity, and SP1 inhibition produces neuroprotective effects in PD models through decreases in MAO B activity, which may be a new neuroprotective therapeutic strategy for PD treatment.

Transcriptome Analysis Reveals Distinct Responses to Physiologic versus Toxic Manganese Exposure in Human Neuroblastoma Cells

“…Thus, in vivo –based systems biology approaches will be needed to test whether upregulation of protein secretion pathway and deficit in mitochondrial function can be used to improve assessment and management of risks of Mn neurotoxicity. The present data, along with the extensive previous use of human SH-SY5Y neuroblastoma cells as a model system for study of neurological disorders (Oguchi et al, 2017; Song and Kim, 2017; Yao et al, 2018), provide a foundation for such research. A second limitation is the use of only one omics technology to interpret adaptive from toxic Mn cellular responses.…”

MiR‐29c protects against inflammation and apoptosis in Parkinson's disease model in vivo and in vitro by targeting SP1

“…Specific protein‐1 (SP1) is a member of the specificity protein/Kruppel‐like factor family that contributes to the regulation of cell growth and apoptosis . Yao et al suggest that SP1 is highly expressed in PD model, and its inhibition can display neuroprotective effects through inactivating monoamine oxidase B (MAO B) . Intriguingly, SP1 was predicted to have complementary sites with miR‐29c in our preliminary researches.…”

“…SP1 was suggested to be a widely expressed DNA‐binding protein containing a C 2 H 2 zinc finger structure, which modulated gene transcription in diverse physiological and pathological processes . Some research had discovered that the expression of SP1 was increased in the brains of patients or models with AD, PD or other neurodegenerative disorders . A prior study also noted that SP1 signalling was significant in ameliorating the neuropathological changes involving PD by the manipulation of LRRK2 .…”

Common genetic variants associated with Parkinson’s disease display widespread signature of epigenetic plasticity

“…1, Supplementary Table 2). Among former some TFs such as FOXA1, NFATC2; Prrx2, SP1 have previously been linked with PD 9–12 .…”