Patients with Chagas' disease, caused by Trypanosoma cruzi infection, exhibit neural degeneration in the acute phase, neuroregeneration in the chronic indeterminate (asymptomatic) phase, and degeneration of neurons in the chronic symptomatic phase. Most patients remain asymptomatic and with signs of neuronal regeneration for years or decades. Some asymptomatic patients progress to the chronic, fatal chronic disease stage. It remains unknown why patients can remain asymptomatic and with signs of neural regeneration for decades while others develop neurodegeneration later in life. Recent studies demonstrate that T. cruzi expresses surface membrane-bound and shed parasite-derived mimic of neurotrophic factors (PDNF), formerly known as neuraminidase/trans-sialidase, that potently promotes survival of several types of neurons, Schwann cells, and astrocytes. A major and wide audience-reaching finding in the previous five years was that PDNF induces survival and differentiation of neurons by binding and activating TrkA nerve growth factor (NGF) receptor tyrosine kinase. This unique result opens up many interesting avenues to understand the molecular basis of a microbial invader of the nervous system, specifically whether T. cruzi, via PDNF, like authentic host growth factors, recognizes other neurotrophin receptors, triggers off neurotransmitter rate-limiting enzymes through Trks receptors, bear neurotrophin motifs that can be exploited as synthetic peptides to reverse neuronal and glial damage, and elicit autoimmune responses to Trks that might activate or inhibit receptor function. The project will utilize a combination of cell biology, biochemistry, genetics, and immunochemical approaches to identify and characterize the interaction of TrkA and other receptors with PDNF and the novel Trk autoantibodies. Most likely, the outcome of the proposed studies will provide insights into the pathogenesis of Chagas' disease, particularly neuroregeneration, and lead to the development of compounds, principally NGF-like peptidomimetics, to treat not only Chagas' disease but also other neurodegenerative disorders such as Parkinson's disease. ? ?
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