Neuroprotective effects of pituitary adenylate cyclase-activating polypeptide (PACAP) in MPP+-induced alteration of translational control in Neuro-2a neuroblastoma cells.
Parkinson's disease (PD) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity are both associated with dopaminergic neuron death in the substantia nigra. Although a variety of evidence has shown that degenerative cells have apoptotic features, the role of apoptosis in disease pathology remains controversial. The 1-methyl-4-phenylpyridinium ion (MPP(+)), a metabolite of MPTP, was recently shown to alter the expression of proteins involved in translational control. The initiation step of translational control is regulated by a cascade of phosphorylation affecting proteins of the antiapoptotic way controlled by mammalian target of rapamycin (mTOR) and of the proapoptotic way controlled by double-stranded RNA protein-dependent kinase (PKR). A study showed that MPP(+) induced an increase in eIF2alpha phosphorylation, leading to inhibition of protein synthesis.


OBJECTIVE
(1) to assess the effects of MPP(+) toxicity on molecular factors of PKR and mTOR signaling pathways in murine neuroblastoma cells, and (2) to examine the ability of VIP and PACAP peptides to counteract the MPP(+) toxicity. Our findings showed that MPP(+) induced phosphorylation of eIF2alpha and significantly reduced the expression of phosphorylated mTOR, p70S6K, eIF4E, and 4E-BP1, suggesting its toxicity in controlling protein synthesis. Furthermore, the VIP peptide had no effect on either the PKR or the mTOR signaling pathway. On the contrary, the PACAP 27 neuropeptide prevented MPP(+)-induced eIF2alpha phosphorylation and blocked MPP(+) toxicity in molecular factors of the mTOR pathway. And last, PACAP 27 seemed to protect Neuro-2a cells from the apoptotic process as assessed by the decreased nuclear condensation after DAPI staining. These results could open new paths of research of PACAP in PD.
Deguil
Julie
J
Groupe de Recherche sur le Vieillissement Cérébral GReViC, Pôle de Biologie Santé, Poitiers, France.
Jailloux
David
D
Page
Guylène
G
Fauconneau
Bernard
B
Houeto
Jean-Luc
JL
Philippe
Michel
M
Muller
Jean-Marc
JM
Pain
Stéphanie
S
D000818:Animals; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D005456:Fluorescent Dyes; D007211:Indoles; D020267:MPTP Poisoning / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D009447:Neuroblastoma / Q000473:pathology; D009479:Neuropeptides / Q000494:pharmacology; D018696:Neuroprotective Agents; D010766:Phosphorylation; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000494:pharmacology*; D014176:Protein Biosynthesis; D011494:Protein Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology
D005456:Fluorescent Dyes; D007211:Indoles; D009479:Neuropeptides; D018696:Neuroprotective Agents; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D014660:Vasoactive Intestinal Peptide; C007293:DAPI; D011494:Protein Kinases; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D053148:Caspase 3