Understanding how ‘neurotrophic’ signals instruct the development of the brain cells which die in Parkinson’s disease.
Blog by Shane V. Hegarty, BSc, PhD. Post-Doctoral Research Fellow, Department of Anatomy and Neuroscience, UCC.
Ten million people worldwide have been diagnosed with Parkinson’s disease (PD). Those suffering with this disease progressively lose the ability to control their movements. PD has no known cause, however the biggest risk factor for developing the disease is ageing. Terrifyingly, the incidence of PD is set to double in the next 20 years as people are living longer. Despite the relentless progression of PD, both in disease-severity for patients and in numbers-affected worldwide, and despite intense research efforts, PD remains incurable.
In PD, a single population of brain cells, called ‘midbrain dopaminergic neurons’, become diseased and die over time. These brain cells release dopamine, which is the ‘messenger’ that allows midbrain dopaminergic neurons to control our movements. At present, current treatments replace the lost dopamine to provide temporary symptomatic benefits. However, these treatments do not halt or reverse the progression of PD. The fact that PD results from the loss a single population of brain cells provides the promising possibility that a cure for PD may reside in protecting, saving or replacing midbrain dopaminergic neurons. Indeed, the two most promising therapies for modifying PD-progression and maintaining/restoring function in PD patients are: (1) treatment with special brain signals, called ‘neurotrophic factors’, that protect and promote the survival and growth of midbrain dopaminergic neurons; and (2) replacement of the lost midbrain dopaminergic neurons by transplanting new dopaminergic neurons (generated from stem cells) into the brain. In order for these promising therapies to become a reality in PD, we first need to understand how midbrain dopaminergic neurons are born, grow and survive. This understanding would provide a guide for making transplantable dopaminergic neurons from stem cells, and would identify suitable neurotrophic factors for use in PD therapy.
Extensive research has identified ‘GDF5’ and ‘BMP2’ as neurotrophic factors for midbrain dopaminergic neurons. Despite this work, the mechanism by which these neurotrophic factors act to promote the survival and growth of midbrain dopaminergic neurons remained unknown. GDF5 and BMP2 are closely-related members of the same family of extracellular (located outside cells) proteins/‘signals’, which typically recruit ‘Smads’ inside cells to mediate their effects. This research demonstrated that these ‘Smads’ act to mediate the growth-promoting effects of GDF5 and BMP2 in midbrain dopaminergic neurons. We also showed that the specific receptors, which detect the GDF5 and BMP2 signals, are present on midbrain dopaminergic neurons as they develop. This research then identified the exact sub-type of these receptors, called ‘BMP receptor type-1b’, that is important for GDF5- and BMP2-induced promotion of growth. Building on this work, a unique DNA-regulating signal called ‘Smad-interacting protein-1’ was shown to be an important signal for midbrain dopaminergic neuron growth for the first time. Finally, GDF5 and BMP2 were shown to determine the fate of brain stem cells, with GDF5 instructing the production of dopamine in midbrain neurons. Taken together, this PhD research project demonstrated that GDF5 and BMP2 are important neurotrophic factors for the development of midbrain dopaminergic neurons, and that their effects are carried out by Smads in these neurons.