The neuroprotective effect of Activin A and B: implication for neurodegenerative diseases.
Activin is a member of the transforming growth factor-beta superfamily which comprises a growing list of multifunctional proteins that function as modulators of cell proliferation, differentiation, hormone secretion and neuronal survival. This study examined the neuroprotective effect of both Activin A and B in serum withdrawal and oxidative stress apoptotic cellular models and investigated the expression of pro- and anti-apoptotic proteins, which may account for the mechanism of Activin-induced neuroprotection. Here, we report that recombinant Activin A and B are neuroprotective against serum deprivation- and toxin- [either the parkinsonism-inducing neurotoxin, 6-hydroxydopamine (6-OHDA) or the peroxynitrite donor, 3-(4-morpholinyl) sydnonimine hydrochloride (SIN-1)] induced neuronal death in human SH-SY5Y neuroblastoma cells. Furthermore, we demonstrate for the first time that transient transfection with Activin betaA or betaB significantly protect SH-SY5Y and rat pheochromocytoma PC12 cells against serum withdrawal-induced apoptosis. This survival effect is mediated by the Bcl-2 family members and involves inhibition of caspase-3 activation; reduction of cleaved poly-ADP ribose polymerase and phosphorylated H2A.X protein levels and elevation of tyrosine hydroxylase expression. These results indicate that both Activin-A and -B share the potential to induce neuroprotective activity and thus may have positive impact on aging and neurodegenerative diseases to retard the accelerated rate of neuronal degeneration.
Eve Topf and USA National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases Research and Department of Pharmacology, Rappaport Family Research Institute, Technion-Faculty of Medicine, Haifa, Israel.
Lana
L
Kupershmidt
Tamar
T
Amit
Orit
O
Bar-Am
Moussa B H
MB
Youdim
Zeev
Z
Blumenfeld
D028341:Activins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016895:Culture Media, Serum-Free / Q000633:toxicity; D006657:Histones / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008981:Molsidomine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000633:toxicity; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000517:prevention & control; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D016627:Oxidopamine / Q000037:antagonists & inhibitors / Q000633:toxicity; D016716:PC12 Cells; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D014162:Transfection; D014446:Tyrosine 3-Monooxygenase / Q000187:drug effects / Q000378:metabolism
D028341:Activins; D051017:Apoptosis Regulatory Proteins; D016895:Culture Media, Serum-Free; D006657:Histones; D008981:Molsidomine; D018696:Neuroprotective Agents; D016627:Oxidopamine; D011065:Poly(ADP-ribose) Polymerases; D014446:Tyrosine 3-Monooxygenase; C422405:activin A; C044147:activin B; C002385:linsidomine; C475961:gamma-H2AX protein, mouse