title: Downregulation of PMCA2 increases the vulnerability of midbrain neurons to mitochondrial complex I inhibition.
abstract: 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.
authors.affiliation: Institute for Pathobiochemistry, University Medical Center of the Johannes Gutenberg-University Mainz, Duesbergweg 6, 55099 Mainz, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Brendel
authors.affiliation: Institute for Pathobiochemistry, University Medical Center of the Johannes Gutenberg-University Mainz, Duesbergweg 6, 55099 Mainz, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Renziehausen
authors.affiliation: Institute for Pathobiochemistry, University Medical Center of the Johannes Gutenberg-University Mainz, Duesbergweg 6, 55099 Mainz, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Behl
authors.affiliation: Institute for Pathobiochemistry, University Medical Center of the Johannes Gutenberg-University Mainz, Duesbergweg 6, 55099 Mainz, Germany. Electronic address: hajieva@uni-mainz.de.
authors.forename: Parvana
authors.initials: P
authors.lastname: Hajieva
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity; D000818:Animals; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D015536:Down-Regulation; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D008297:Male; D008636:Mesencephalon / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D053499:Plasma Membrane Calcium-Transporting ATPases; D042967:Electron Transport Complex I; C506958:ATP2B2 protein, human; D015655:1-Methyl-4-phenylpyridinium; D002118:Calcium
keywords: Calcium; MPTP; Midbrain neurons; Neuronal vulnerability; PMCA2; Parkinson's disease