Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.4.24.64 (
MPP
)
1,876
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Parkinson's disease is an age-associated disorder characterized by selective degeneration of dopaminergic neurons. The molecular mechanisms underlying the selective vulnerability of this subset of neurons are, however, not fully understood. Employing SH-SY5Y neuroblastoma cells and primary mesencephalic neurons, we here demonstrate a significant increase in cytosolic calcium after inhibition of mitochondrial complex I by means of
MPP
(+), which is a well-established environmental toxin-based in vitro model of Parkinson's disease. This increase in calcium is correlated with a downregulation of the neuron-specific plasma membrane Ca(2+)-ATPase isoform 2 (
PMCA2
). Interestingly, two other important mediators of calcium efflux, sarcoplasmic reticulum Ca(2+)-ATPase (SERCA), and Na(+)-Ca(2+)-exchanger (NCX), remained unaltered, indicating a specific role of
PMCA2
in maintaining calcium homeostasis in neurons. The observed
PMCA2
downregulation was accompanied by reduced levels of phosphorylated CREB protein, an intracellular signaling molecule and transcriptional regulator. In order to investigate the potential influence of
PMCA2
on neuronal vulnerability, experimental downregulation of
PMCA2
by means of siRNA was performed. The results demonstrate a significant impairment of cell survival under conditions of
PMCA2
suppression. Hence, in our cell models increased cytosolic calcium levels as a consequence of insufficient calcium efflux lead to an increased vulnerability of neuronal cells. Moreover, overexpression of
PMCA2
rendered the neurons significantly resistant to complex I inhibition. Our findings point toward a dysregulation of calcium homeostasis in Parkinson's disease and suggest a potential molecular mechanism of neurodegeneration via
PMCA2
.
...
PMID:Downregulation of PMCA2 increases the vulnerability of midbrain neurons to mitochondrial complex I inhibition. 2426 47
