Canonical BMP–Smad Signalling Promotes Neurite Growth in Rat Midbrain Dopaminergic Neurons

Ventral midbrain (VM) dopaminergic (DA) neurons project to the dorsal striatum via the nigrostriatal pathway to regulate voluntary movements, and their loss leads to the motor dysfunction seen in Parkinson’s disease (PD). Despite recent progress in the understanding of VM DA neurogenesis, the factors regulating nigrostriatal pathway development remain largely unknown. The bone morphogenetic protein (BMP) family regulates neurite growth in the developing nervous system and may contribute to nigrostriatal pathway development. Two related members of this family, BMP2 and growth differentiation factor (GDF)5, have neurotrophic effects, including promotion of neurite growth, on cultured VM DA neurons. However, the molecular mechanisms regulating their effects on DA neurons are unknown. By characterising the temporal expression profiles of endogenous BMP receptors (BMPRs) in the developing and adult rat VM and striatum, this study identified BMP2 and GDF5 as potential regulators of nigrostriatal pathway development. Furthermore, through the use of noggin, dorsomorphin and BMPR/Smad plasmids, this study demonstrated that GDF5- and BMP2-induced neurite outgrowth from cultured VM DA neurons is dependent on BMP type I receptor activation of the Smad 1/5/8 signalling pathway

Nociceptin/orphanin FQ inhibits the survival and axon growth of midbrain dopaminergic neurons through a p38-MAPK dependent mechanism

Nociceptin/orphanin FQ (N/OFQ) is an opioid-like neuropeptide that binds and signals through a G-protein-coupled receptor called the N/OFQ peptide (NOP) receptor. N/OFQ and the NOP receptor are expressed in the midbrain and have been implicated in the pathogenesis of Parkinson’s disease (PD). Genetic removal of the N/OFQ precursor partially protects midbrain dopaminergic neurons from 1-methyl-4-phenylpyridine-induced toxicity, suggesting that endogenous N/OFQ may be detrimental to dopaminergic neurons. However, whether N/OFQ directly affects the survival and growth of dopaminergic neurons is unknown. Here, we show that N/OFQ has a detrimental effect on the survival of dopaminergic neurons and the growth of their axons in primary cultures of the E14 rat ventral mesencephalon. N/OFQ potentiates the effects of the neurotoxins 6-hydroxydopamine and 1-methyl-4-phenylpyridinium through p38-MAPK signalling. We also show that like α-synuclein, there is a significant reduction in N/OFQ messenger RNA (mRNA) expression in the midbrain of patients with Parkinson’s disease. These results demonstrate for the first time that N/OFQ is detrimental to the survival and growth of dopaminergic neurons and that its expression is altered in the midbrain of patients with Parkinson’s disease