The midbrain dopaminergic pathways
The midbrain dopaminergic pathways originate from the ventral tegmental area (VTA) and substantia nigra pars compact (SNc) and are the major source of dopamine in the brain. Named after their place of origin and target innervation area, the mesocortical, the mesolimbic and the nigrostriatal pathway play a central role in brain functions and disorders.
BMP5/7 protect dopaminergic neurons in an alpha-synuclein mouse model of Parkinson's disease
Parkinson's disease (PD) affects over 10 million people worldwide and is characterized by the progressive degeneration of midbrain dopaminergic neurons, leading to severe motor impairments. A central hallmark of PD pathogenesis is the misfolding and aggregation of the protein alpha-synuclein, which forms toxic clumps within these dopamine-producing cells. While current PD therapies alleviate clinical symptoms, their efficacy declines significantly in advanced stages of the disease, and they fail to slow or halt ongoing neurodegeneration.
Based on our previous findings that bone morphogenetic protein (BMP) pathway activation promotes the neurogenesis of midbrain dopaminergic neurons in vivo as well as in human induced pluripotent stem cells (iPSCs) and neural stem cells, we hypothesized that BMP signaling could also exert neuroprotective effects. To test this, we co-administered BMP5/7 alongside alpha-synuclein in a mouse model of PD. Remarkably, we found that BMP5/7 treatment efficiently prevents alpha-synuclein accumulation, preserves dopaminergic neurons, and rescues associated motor deficits. Moving forward, our laboratory is focusing on deciphering whether the BMP pathway modulate the genetic risk of Parkinson's disease, and evaluating whether BMP5/7 can drive neurorestorative effects when delivered to damaged neurons after the onset of motor symptoms.
Immunostaining of substantia nigra pars compacta dopaminergic neurons visualized by tyrosine hydroxylase (TH). BMP5/7 delivered by a gene therapy approach into the striatum can reverse the loss of dopaminergic neurons caused by the viral overexpression of human mutated A53T α-synuclein (A). The data in graphs represent the mean ± standard error of the mean (SEM) (B). *p < 0.05, **p < 0.01, ***p<0.001 Fisher’s LSD post-hoc test, after significant one-way ANOVA
Reference: Vitic et al., BMP5/7 protect dopaminergic neurons in an alpha-synuclein mouse model of Parkinson's disease, Brain. 2021 Mar 3;144(2):e15
The BMP/SMAD pathway promotes neurogenesis of midbrain dopaminergic neurons in vivo and in human induced pluripotent and neural stem cells
In a previous project we identified BMP/SMAD signaling as a novel essential pathway regulating the development of midbrain dopaminergic neurons in vivo and provided insights into the molecular mechanisms of this process. Importantly, we could show with our collaborators that BMPs increase robustly the differentiation of human induced pluripotent and induced neural stem cells to dopaminergic neurons. BMP/SMAD are routinely inhibited in initial stages of stem cell differentiation protocols currently being developed for Parkinson's disease cell replacement therapies. Therefore, our findings on opposing roles of the BMP/SMAD pathway during in vitro dopaminergic neurogenesis might improve these procedures significantly.
Reference: Jovanovic et al., BMP/SMAD pathway promotes neurogenesis of midbrain dopaminergic neurons in vivo and in human induced pluripotent and neural stem cells The Journal of Neuroscience 2018 Feb 14;38(7):1662-1676. * Selected as cover story.