Trypanosome trans-sialidase mediates neuroprotection against oxidative stress, serum/glucose deprivation, and hypoxia-induced neurite retraction in Trk-expressing PC12 cells.
Trypanosome trans-sialidase (TS) is a sialic acid-transferring enzyme and a novel ligand of tyrosine kinase (TrkA) receptors but not of neurotrophin receptor p75NTR. Here, we show that TS targets TrkB receptors on TrkB-expressing pheochromocytoma PC12 cells and colocalizes with TrkB receptor internalization and phosphorylation (pTrkB). Wild-type TS but not the catalytically inactive mutant TSDeltaAsp98-Glu induces pTrkB and mediates cell survival responses against death caused by oxidative stress in TrkA- and TrkB-expressing cells like those seen with nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). These same effects are not observed in Trk deficient PC12(nnr5) cells, but are re-established in PC12(nnr5) cells stably transfected with TrkA or TrkB, are partially blocked by inhibitors of tyrosine kinase (K-252a), mitogen-activated protein/mitogen-activated kinase (PD98059) and completely blocked by LY294002, an inhibitor of phosphatidylinositol 3-kinase (PI3K). Both TrkA- and TrkB-expressing cells pretreated with TS or their natural ligands are protected against cell death caused by serum/glucose deprivation or from hypoxia-induced neurite retraction. The cell survival effects of NGF and BDNF against oxidative stress are significantly inhibited by the neuraminidase inhibitor, Tamiflu. Together, these observations suggest that trypanosome TS mimics neurotrophic factors in cell survival responses against oxidative stress, hypoxia-induced neurite retraction and serum/glucose deprivation.
Woronowicz
Alicja
A
Department of Microbiology and Immunology, Queen's University, Kingston, Ontario, Canada K7L3N6.
Amith
Schammim Ray
SR
Davis
Vanessa W
VW
Jayanth
Preethi
P
De Vusser
Kristof
K
Laroy
Wouter
W
Contreras
Roland
R
Meakin
Susan O
SO
Szewczuk
Myron R
MR
D000818:Animals; D002470:Cell Survival; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006023:Glycoproteins / Q000378:metabolism*; D000860:Hypoxia; D020932:Nerve Growth Factor / Q000378:metabolism; D009439:Neuraminidase / Q000378:metabolism*; D053139:Oseltamivir / Q000494:pharmacology; D018384:Oxidative Stress; D016716:PC12 Cells; D051381:Rats; D020813:Receptor, trkB / Q000378:metabolism*; D044967:Serum / Q000378:metabolism*; D014349:Trypanosoma cruzi / Q000378:metabolism*
D004791:Enzyme Inhibitors; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006023:Glycoproteins; D053139:Oseltamivir; D020932:Nerve Growth Factor; D020813:Receptor, trkB; C069715:trans-sialidase; D009439:Neuraminidase; D005947:Glucose