Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
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Query: UMLS:C0030567 (
Parkinson's disease
)
63,064
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The neurotoxins paraquat (PQ) and dopamine (DA or 6-OHDA) cause apoptosis of dopaminergic neurons in the substantia nigra pars compacta (SNpc), reproducing an important pathological feature of
Parkinson's disease
(PD). Secretogranin III (
SCG3
), a member of the multifunctional granin family, plays a key role in neurotransmitter storage and transport and in secretory granule biogenesis, which involves the uptake of exogenous toxins and endogenous "toxins" in neuroendocrine cells. However, the molecular mechanisms of neurotoxin-induced apoptosis in dopaminergic neurons and the role of
SCG3
-associated signaling pathways in neuroendocrine regulation are unclear. To address this, we used PQ- and DA-induced apoptosis in SH-SY5Y human dopaminergic cells as an in vitro model to investigate the association between
SCG3
expression level and apoptosis.
SCG3
was highly expressed in SH-SY5Y cells, and
SCG3
mRNA and protein levels were dramatically decreased after PQ treatment. Apoptosis induced by PQ is associated with caspase activation and decreased
SCG3
expression, and restoration of
SCG3
expression is observed after treatment with caspase inhibitors. Overexpressed
SCG3
in nonneuronal cells and endogenous
SCG3
in SH-SY5Y cells are cleaved into specific fragments by recombinant caspase-3 and -7, but the fragments were not detected in PQ-treated SH-SY5Y cells. Therefore,
SCG3
may be involved in apoptosis signal transduction as a caspase substrate, leading to loss of its original biological functions. In addition,
SCG3
may be a pivotal component of the neuroendocrine pathway and play an important role in neuronal communication and neurotransmitter release, possibly representing a new potential target in the course of PD pathogenesis.
...
PMID:Dysregulated expression of secretogranin III is involved in neurotoxin-induced dopaminergic neuron apoptosis. 2298 61
Environmental neurotoxins such as paraquat (PQ), manganese, and 1-1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are associated with a higher risk of
Parkinson's disease
(PD). These parkinsonian toxins exert certain common toxicological effects on astroglia; however, their role in the regulatory functions of astroglial secretory proteins remains unclear. In a previous study, we observed that secretogranin II (SCG2) and secretogranin III (
SCG3
), which are important components of the regulated secretory pathway, were elevated in PQ-activated U118 astroglia. In the current study, we used the parkinsonian toxins dopamine (DA), active metabolite of MPTP (MPP
+
), MnCl
2
, and lipopolysaccharide (LPS) as inducers, and studied the potential regulation of SCG2 and
SCG3
. Our results showed that all the parkinsonian toxins except LPS affected astroglial viability but did not cause apoptosis. Exposure to DA, MPP
+
, and MnCl
2
upregulated glial fibrillary acidic protein (GFAP), a marker for astrocyte activation, and stimulated the levels of several astrocytic-derived factors. Further, DA, MPP
+
, and MnCl
2
exposure impeded astroglial cell cycle progression. Moreover, the expression of
SCG3
was elevated, while its exosecretion was inhibited in astroglia activated by parkinsonian toxins. The level of SCG2 remained unchanged. In combination with our previous findings, the results of this study indicate that
SCG3
may act as a cofactor in astrocyte activation stimulated by various toxins, and the regulation of
SCG3
could be involved in the toxicological mechanism by which parkinsonian toxins affect astroglia.
...
PMID:Secretogranin III upregulation is involved in parkinsonian toxin-mediated astroglia activation. 3240 59
