PDNF, a human parasite-derived mimic of neurotrophic factors, prevents caspase activation, free radical formation, and death of dopaminergic cells exposed to the Parkinsonism-inducing neurotoxin MPP+.
The neuraminidase/trans-sialidase of Trypanosoma cruzi, the agent of Chagas' disease, promotes differentiation and survival of growth factor-deprived neuronal and glial cells. To gain further insights into the possible neuroprotection of this parasite-derived counterpart of neurotrophic factors (PDNF), we sought to determine whether it mimics growth factors in a cellular model of neurodegenerative diseases. Ascertaining cell viability by morphology, vital dye exclusion, mitochondrial reducing function, and absence of DNA fragmentation, we show here that PDNF rescues from death two dopaminergic neuronal cell lines and one differentiated immortalized mesencephalic neurons exposed to the neurotoxin 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) and its toxic metabolite, 1-methyl-4-phenylpyridinium (MPP+), both widely used in models of Parkinson's disease. We further show that PDNF promoted survival at concentrations comparable to bona fide growth factors in a MAPK/Erk activation-dependent manner. PDNF also strongly suppresses the overproduction of MPTP-induced reactive oxygen species (ROS), and the activation of both initiator caspase-9 and effector caspase-3. This down-regulation of ROS and caspases explains, at least in part, the PDNF-induced salvaging of the dopaminergic cells from the Parkinsonism-promoting toxin, confirming the novel and striking functional mimicry by the trypanosome neuraminidase of host growth factors in a cellular model of neurodegeneration.
Parasitology Research Center, Department of Pathology, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA.
Marina V
MV
Chuenkova
Miercio A
MA
Pereira
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D000818:Animals; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects* / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D018716:Molecular Mimicry / Q000502:physiology; D009414:Nerve Growth Factors / Q000494:pharmacology* / Q000627:therapeutic use; D009439:Neuraminidase / Q000494:pharmacology* / Q000627:therapeutic use; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology; D016716:PC12 Cells; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D051381:Rats; D014349:Trypanosoma cruzi / Q000201:enzymology
D005609:Free Radicals; D009414:Nerve Growth Factors; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D009439:Neuraminidase; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine