BMP 5/7 protect dopaminergic neurons in a mouse model of Parkinson’s disease

Claude Brodski Zagorka Vitic ¹ Hasem Safory ² Vukasin M. Jovanovic ³ Alexandra Stavsky ¹ Joy Kahn ¹ Alona Kuzmina ⁴ Daniel Gitler ¹ Ran Taube ⁴ Simone Engelender ² Claude Brodski ¹

¹Department of Physiology and Cell Biology, Zlotowski Center for Neuroscience, Faculty of Health Sciences, Ben-Gurion University of the Negev, 84105 Be'er Sheva, Israel
²Dept. of Biochemistry, The B. Rappaport Faculty of Medicine and Institute of Medical Research, Technion-Israel Institute of Technology, Haifa 31096, Israel
³National Center for Advancing Translational Sciences (NCATS), Stem Cell Translation Laboratory (SCTL), National Institutes of Health (NIH), Rockville, MD 20850, USA
⁴Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, 84105 Be'er Sheva, Israel

Parkinson’s disease (PD) is characterized by progressive motor impairments caused by the degeneration of dopaminergic (DA) neurons of the substantia nigra pars compacta (SN). Aggregation of the protein α-synuclein is thought to play a key role in the etiology of PD and loss of SN neurons. Currently there is no cure for PD and despite great efforts a disease-modifying therapy for PD is not yet available.
Neurotrophic factors are prime candidates for the development of disease-modifying therapies based on their properties to restore and maintain the functional integrity of neurons that are dysfunctional but not lost. Clinical trials, mostly using a gene therapy approach, demonstrated that these proteins are generally safe, however, they have not been able to meet their primary endpoint. Converging evidence suggests that this lack of efficacy is associated with the inability of the so far tested neurotrophic factors to protect SN neurons against α-synuclein-induced neurotoxicity.
Previously, we found that bone morphogenetic proteins 5/7 (BMP5/7) promotes neurogenesis of DA neurons in vivo and in human induced pluripotent and neural stem cells. Now, we report that in a viral α-synuclein overexpression PD mouse model, BMP5/7 delivered by lentiviral vectors prevent α-synuclein induced loss of DA neurons, projections, motor symptoms and associated gliosis. Moreover, we demonstrate that BMP5/7 treatment significantly reduce α-synuclein accumulation.
Taken together, BMP5/7, delivered by a gene therapy approach, are new promising potential therapeutics for Parkinson’s disease that could change the trajectory of the disorder (Vitic et al., 2020, Brain).