Chagas' disease parasite-derived neurotrophic factor activates cholinergic gene expression in neuronal PC12 cells.
A parasite-derived neurotrophic factor (PDNF) produced by the Chagas' disease parasite Trypanosoma cruzi binds nerve growth factor (NGF) receptor TrkA, increasing receptor autophosphorylation, and activating phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK/Erk) pathways, and transcription factor CREB. The end-result is enhanced survival and neuritogenesis of various types of neurons. PDNF also enhances the expression and activity of tyrosine hydroxylase, a rate limiting enzyme in the synthesis of dopamine and other catecholamine neurotransmitters. It remains unknown, however, if PDNF alters expression and metabolism of acetylcholine (ACh), a neurotransmitter thought to play a role in Chagas' disease progression. Here we demonstrate that PDNF stimulates mRNA and protein expression of choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT), which are critical for synthesis and storage of ACh. Stimulation requires functional TrkA because it did not occur in cell mutants that lack the receptor and in TrkA-expressing wild-type cells treated with K252a, an inhibitor of TrkA kinase activity. It also requires TrkA-dependent PI3K and MAPK/Erk signaling pathways because PDNF stimulation of cholinergic transcripts is abolished by specific pharmacological inhibitors. Furthermore, the cholinergic actions of PDNF were reproduced by PDNF-expressing extracellular T. cruzi trypomastigotes at the start of host cell invasion. In contrast, host cells bearing intracellular T. cruzi showed decreased, rather than increased, cholinergic gene expression. These results suggest that T. cruzi invasion of the nervous system alters cholinergic gene expression and that could play a role in neuropathology, and/or lack thereof, in Chagas' disease patients.
Akpan
Nsikan
N
Parasitology Research Center, Department of Pathology, Tufts University School of Medicine, Boston, MA 02111, USA.
Caradonna
Kacey
K
Chuenkova
Marina V
MV
PereiraPerrin
Mercio
M
D000818:Animals; D015153:Blotting, Western; D014355:Chagas Disease / Q000378:metabolism* / Q000503:physiopathology*; D002795:Choline O-Acetyltransferase / Q000096:biosynthesis; D002799:Cholinergic Fibers / Q000378:metabolism / Q000382:microbiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D005786:Gene Expression Regulation; D020932:Nerve Growth Factor / Q000378:metabolism*; D016716:PC12 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015800:Protozoan Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D020917:Receptor, trkA / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D014349:Trypanosoma cruzi / Q000502:physiology; D050494:Vesicular Acetylcholine Transport Proteins / Q000096:biosynthesis
D015800:Protozoan Proteins; D012333:RNA, Messenger; D050494:Vesicular Acetylcholine Transport Proteins; D020932:Nerve Growth Factor; D002795:Choline O-Acetyltransferase; D019869:Phosphatidylinositol 3-Kinases; D020917:Receptor, trkA; D048049:Extracellular Signal-Regulated MAP Kinases