Abstract
We have studied the role of the tumor necrosis factor superfamily member APRIL in the development of embryonic mouse midbrain dopaminergic neurons in vitro and in vivo. In culture, soluble APRIL enhanced axon growth during a window of development between E12 and E14 when nigrostriatal axons are growing to their targets in the striatum in vivo. April transcripts were detected in both the striatum and midbrain during this period and at later stages. The axon growth–enhancing effect of APRIL was similar to that of glial cell-derived neurotrophic factor (GDNF), but in contrast to GDNF, APRIL did not promote the survival of midbrain dopaminergic neurons. The effect of APRIL on axon growth was prevented by function-blocking antibodies to one of its receptors, BCMA (TNFRSF13A), but not by function-blocking antibodies to the other APRIL receptor, TACI (TNFRSF13B), suggesting that the effects of APRIL on axon growth are mediated by BCMA. In vivo, there was a significant reduction in the density of midbrain dopaminergic projections to the striatum in April−/− embryos compared with wild type littermates at E14. These findings demonstrate that APRIL is a physiologically relevant factor for the nigrostriatal projection. Given the importance of the degeneration of dopaminergic nigrostriatal connections in the pathogenesis and progression of Parkinson's disease, our findings contribute to our understanding of the factors that establish nigrostriatal integrity.
Highlights
Parkinson's disease is a neurodegenerative disease that affects about 1% of the population over the age of 60
In addition to setting up cultures with and without APRIL, we set up cultures supplemented with glia cell-derived neurotrophic factor (GDNF) as a positive control because GDNF has been shown to enhance axon growth from cultured midbrain dopaminergic neurons and to enhance the survival of these neurons in vitro
Saturating concentrations of APRIL and GDNF in combination did not have an additive effect on axon growth, suggesting that they affect the same population of dopaminergic neurons
Summary
Parkinson's disease is a neurodegenerative disease that affects about 1% of the population over the age of 60 It is characterized by progressive and disabling motor symptoms that are due to the degeneration and loss of the dopaminergic neurons of the substantia nigra pars compacta that project to the striatum (Lindholm et al, 2016). While some open-label trials have reported modest symptomatic improvement, no efficacy has been reported in any extensive double-blind trial (Olanow et al, 2015) This large body of work on GDNF and limited studies of other factors that exert trophic actions on dopaminergic neurons highlight the need to identify additional factors that act on these neurons, especially those that exert physiological relevant trophic actions in vivo
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