Susan R Goulding1, Aideen M Sullivan2, Gerard W O'Keeffe3, Louise M Collins4. 1. Department of Biological Sciences, Cork Institute of Technology, Cork, Ireland; Department of Anatomy and Neuroscience & Cork Neuroscience Centre, University College Cork, Cork, Ireland. 2. Department of Anatomy and Neuroscience & Cork Neuroscience Centre, University College Cork, Cork, Ireland. 3. Department of Anatomy and Neuroscience & Cork Neuroscience Centre, University College Cork, Cork, Ireland. Electronic address: g.okeeffe@ucc.ie. 4. Department of Anatomy and Neuroscience & Cork Neuroscience Centre, University College Cork, Cork, Ireland; Department of Physiology, University College Cork, Cork, Ireland. Electronic address: l.collins@ucc.ie.
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.
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.
Authors: Susan R Goulding; Martin Lévesque; Aideen M Sullivan; Louise M Collins; Gerard W O'Keeffe Journal: Mol Neurobiol Date: 2021-03-12 Impact factor: 5.590
Authors: Martina Mazzocchi; Sean L Wyatt; Daniela Mercatelli; Michele Morari; Noelia Morales-Prieto; Louise M Collins; Aideen M Sullivan; Gerard W O'Keeffe Journal: Front Cell Dev Biol Date: 2019-09-13
Authors: Jayanth Anantha; Susan R Goulding; Eszter Tuboly; Adam G O'Mahony; Gerard M Moloney; Gareth Lomansey; Cathal M McCarthy; Louise M Collins; Aideen M Sullivan; Gerard W O'Keeffe Journal: Mol Neurobiol Date: 2021-10-08 Impact factor: 5.682
Authors: Sophie Casey; Kate Goasdoue; Stephanie M Miller; Gary P Brennan; Gary Cowin; Adam G O'Mahony; Christopher Burke; Boubou Hallberg; Geraldine B Boylan; Aideen M Sullivan; David C Henshall; Gerard W O'Keeffe; Catherine Mooney; Tracey Bjorkman; Deirdre M Murray Journal: Mol Neurobiol Date: 2020-07-27 Impact factor: 5.682
Authors: Jayanth Anantha; Susan R Goulding; Sean L Wyatt; Ruth M Concannon; Louise M Collins; Aideen M Sullivan; Gerard W O'Keeffe Journal: iScience Date: 2020-08-12