What is Ghrelin and why is it important?
Parkinson’s disease is characterised by a loss of dopaminergic neurons within areas involved in motor coordination, primarily resulting in motor deficits. Ghrelin has a role in activating dopaminergic neurons by acting as a ligand for the growth hormone secretagogue receptor (GHSR). GHSR is found throughout the body but can also be found in small amounts in the brain, particularly in the Pars Compacta portion of the substantia nigra (SNc).
Ghrelin activation of SNc dopaminergic neurons feeds into an area within the basal ganglia, known as the striatum. This area plays a central role in motor action and planning, communicating with other brain areas, including the thalamus which relays these motor signals to areas of the cortex involved in movement generation and coordination.
Activation of dopamine neurons in the SNc causes an increase in the enzyme tyrosine hydroxylase in the midbrain, which increases dopamine turnover in the striatum.
Higher numbers of GHSR and tyrosine hydroxylase co-expressing neurons have been identified in the SNc than other parts of the brain. These lost neurons primarily project into the SNc affecting its influence on the basal ganglia’s motor coordination.
这项研究做了什么？
To study the changes in Ghrelin within Parkinson’s disease patients, Professor Narita等从帕金森患者的皮肤细胞中产生了疾病特异性多巴胺能神经元，其疾病是由于遗传突变的结果PARK2基因。这使得disea重演的se in a human relatable model as the disease phenotypes were retained in the generated neurons.
They found a significant decrease in the mRNA levels and protein expression of the GHS receptors, in both the disease specific iPSCs generated from patient samples, and those generated in vivo using the technology CRISPR/Cas9 to introduce thePARK2gene mutation.
In order to investigate whether direct inhibition of GHSR function in the brain can affect motor coordination, researchers conducted an体内evaluation in a normal mouse model. These mice were injected in the brain with a GHSR agonist ([D-lys3]-GHRP-6). This induced a dose dependent impairment of motor coordination, demonstrated by the reduced time for which the mouse could stay on in a rotarod test.
This evidence, along with the down regulation of GHSR seen in in the iPSCs, suggests that deficits in GHSR activity in the SNc caused by neuronal loss may be part of the symptomatic development of Parkinson’s disease.
But how might this implicate Parkinson’s patients in the future?
尽管可能需要进一步的分析来确切确定PARK2突变如何影响GHSR表达，但很明显，在多巴胺能神经元中，Down降低了生长素蛋白受体的受体在神经元的初始功能障碍中起作用，从而导致运动功能障碍在帕金森氏症中看到。
Identification of this biochemical change could provide an alternative route of therapeutic targets for Parkinson’s patients. The use of Ghrelin and its pathway as a therapeutic route is supported by previous studies which showed that Ghrelin restricts dopamine cell loss in the SNc and striatum in mice due to its neuroprotective properties.
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