Enhancement of tyrosine hydroxylase expression and activity by Trypanosoma cruzi parasite-derived neurotrophic factor

A parasite-derived protein, PDNF, produced by the Chagas' disease agent Trypanosoma cruzi, functionally mimics mammalian neurotrophic factors by delaying apoptotic death and promoting survival and differentiation of neurons, including dopaminergic cells, through the activation of nerve growth factor receptor TrkA. Because it is well established that neurotrophic factors regulate enzymes involved in the biosynthesis of neurotransmitters, we examined whether PDNF could also directly activate tyrosine hydroxylase (TH), a rate-limiting enzyme in the synthesis of dopamine and other catecholamine neurotransmitters. We found that primary cultures of rat ventral mesencephalon responded to PDNF by increasing the number of TH-positive neurons and, most importantly, preserved expression of TH in neurons treated with Parkinson disease-inducing neurotoxin 1-methyl-4-phenyl pyridinium (MPP+). In dopaminergic PC12 cells, PDNF induced TH transcription via CRE element in TH promoter followed by significant increase in TH protein and expansion of TH-positive cell population. Furthermore, PDNF stimulated TH enzymatic activity by enhancing phosphorylation of seryl residues 31 and 40 through the activation of MAPK/Erk1/2 and cAMP-dependent protein kinase A signaling, respectively. Therefore, our results indicate that PDNF, in addition to its functioning as survival and differentiation-promoting factor for dopaminergic neuronal cells, can directly influence activity of the rate-limiting enzyme that underlies catecholamine biosynthetic cascade. This novel feature of PDNF should help understand the mechanism of neuronal function altered by T. cruzi infection, specifically neurotransmitter secretion. In addition, the findings have potential implications in the therapy of Chagas' and other neurodegenerative disorders.