Abstract
The SGT1 protein is highly expressed in the mammalian brain, particularly in neurons of the hippocampus and cortex, and in Purkinje cells of the cerebellum. There are literature data indicating that the protein may be involved in pathogenesis of neurodegenerative disorders such as Parkinson’s disease (PD). In the present work we have found that SGT1 protected cells from the toxicity of rotenone, an agent that evokes behavioral and histopathological symptoms of PD. To gain more insight into the possible mechanism underlying the protective action of SGT1 we looked at α-synuclein subcellular distribution in HEK293 cells with an altered SGT1 level. By immunofluorescent staining we have found that in HEK293 cells overexpressing SGT1 α-synuclein was mainly localized in the cytoplasm while in control cells it was present in the nucleus. Accordingly, when SGT1 expression was silenced, α-synuclein was predominantly present in the nucleus. These results were then confirmed by subcellular fractionation and Western blot analysis. Moreover, we have found that altered level of SGT1 in HEK293 cells influenced the expression of PD related genes, PINK1 and PARK9. Altogether, our results point to SGT1 as an important factor that might be involved in the pathogenesis of Parkinson’s disease (PD).
Highlights
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the presence of characteristic intracellular inclusions, called Lewy bodies (LBs), composed of misfolded α-synuclein, and by selective loss of dopaminergic neurons in substantia nigra.The majority of PD cases are sporadic in origin
We checked whether SGT1, as a co-chaperone of Hsp90, has an effect on the viability of HEK293 cells treated with rotenone, an agent that evokes behavioral and histopathological symptoms similar to those observed in PD [24]
Based on the results presented in this work we suggest that SGT1-dependent changes in α-synuclein subcellular localization and PTEN-induced kinase 1 (PINK1) and PARK9 gene expression strongly argue for the involvement of SGT1 in the pathogenesis of PD, more studies are required to elucidate its role in signaling pathways leading to PD development
Summary
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the presence of characteristic intracellular inclusions, called Lewy bodies (LBs), composed of misfolded α-synuclein, and by selective loss of dopaminergic neurons in substantia nigra.The majority of PD cases are sporadic in origin. Previous studies have shown that under physiological conditions α-synuclein is involved in regulating membrane lipid content, vesicle trafficking, dopamine metabolism or SNARE-dependent complex assembly [2]. It has been shown that nuclear α-synuclein promotes neurotoxicity by inhibiting histone acetylation, while sequestration of α-synuclein in the cytoplasm is protective [4]. Such effect can be due to the involvement of α-synuclein in regulation of transcription through binding to DNA [7], histones [8] and chromatin [9]. It has been shown that α-synuclein is involved in downregulation of Nurr, a Biomolecules 2021, 11, 1675.
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