Abstract
Introduction: α-synuclein-induced degeneration of dopaminergic neurons has been proposed to be central to the early progression of Parkinson's disease. This highlights the need to identify factors that are neuroprotective or neuroregenerative against α-synuclein-induced degeneration. Due to their potent neurotrophic effects on nigrostriatal dopaminergic neurons, we hypothesized that members of the bone morphogenetic protein (BMP) family have potential to protect these cells against α-synuclein. Methods: To identify the most relevant BMP ligands, we used unbiased gene co-expression analysis to identify all BMP family members having a significant positive correlation with five markers of dopaminergic neurons in the human substantia nigra (SN). We then tested the ability of lead BMPs to promote neurite growth in SH-SY5Y cells and in primary cultures of ventral mesencephalon (VM) dopaminergic neurons, treated with either 6-OHDA or MPP+, or overexpressing wild-type or A53T α-synuclein. Results: Only the expression of BMP2 was found to be significantly correlated with multiple dopaminergic markers in the SN. We found that BMP2 treatment promoted neurite growth in SH-SY5Y cells and in dopaminergic neurons. Moreover, BMP2 treatment promoted neurite growth in both SH-SY5Y cells and VM neurons, treated with the neurotoxins 6-OHDA or MPP+. Furthermore, BMP2 promoted neurite growth in cells overexpressing wild-type or A53T-α-synuclein. Conclusion: These findings are important given that clinical trials of two neurotrophic factors, GDNF and neurturin, have failed to meet their primary endpoints. Our findings are a key first step in rationalising the further study of BMP2 as a potential neurotrophic factor in α-synuclein-based translational models of Parkinson's disease.
Disciplines
Biology | Life Sciences | Neuroscience and Neurobiology
DOI
10.1016/j.parkreldis.2019.04.008
Full Publication Date
July 2019
Publisher
Elsevier
Funder Name 1
Cork Institute of Technology
Award Number 1
R00094948
Funder Name 2
Science Foundation Ireland
Award Number 2
15/CDA/3498
Resource Type
journal article
Access Rights
open access
License Condition
This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.
Alternative Identifier
http://www.sciencedirect.com/science/article/pii/S1353802019302032
Recommended Citation
Goulding, S.R. et al., 2019. Gene co-expression analysis of the human substantia nigra identifies BMP2 as a neurotrophic factor that can promote neurite growth in cells overexpressing wild-type or A53T α-synuclein. Parkinsonism & Related Disorders, 64, pp.194–201. Available at: http://dx.doi.org/10.1016/j.parkreldis.2019.04.008.
Publication Details
Parkinsonism & Related Disorders.
© 2019 Elsevier Ltd.