Chagas' disease parasite-derived neurotrophic factor activates cholinergic gene expression in neuronal PC12 cells
| Autor: | Marina V. Chuenkova, Nsikan Akpan, Kacey L. Caradonna, Mercio PereiraPerrin |
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| Rok vydání: | 2008 |
| Předmět: |
MAPK/ERK pathway
Trypanosoma cruzi Vesicular Acetylcholine Transport Proteins Blotting Western Protozoan Proteins Fluorescent Antibody Technique Gene Expression Tropomyosin receptor kinase A Biology PC12 Cells Article Choline O-Acetyltransferase Phosphatidylinositol 3-Kinases Neurotrophic factors Vesicular acetylcholine transporter Nerve Growth Factor Animals Chagas Disease RNA Messenger Receptor trkA Extracellular Signal-Regulated MAP Kinases Molecular Biology Reverse Transcriptase Polymerase Chain Reaction General Neuroscience Molecular biology Choline acetyltransferase Rats Nerve growth factor Cholinergic Fibers Gene Expression Regulation Cholinergic Neurology (clinical) Signal transduction Developmental Biology Signal Transduction |
| Zdroj: | Brain research. 1217 |
| ISSN: | 0006-8993 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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