Of course, PFS and dyskinesia are completely different. Dyskinesia itself bears no relation to PFS.
However, a part of mechanism of PFS might be similar to the mechanism of dyskinesia which can be explained by the two-hit theory.
And first and foremost the method of this research which elucidate the cause and mechanism of dyskinesia certainly be usuful to figure out the cause and mechanism of PFS.
So, I really really want someone to inform this study of our scientists! This method is surely usuful! It is not more difficult than genetic research.
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The auther of this study says as follow:
(google translation)
Dyskinesia, which is treated in the field of neurology, is caused by long-term administration of L-DOPA, a drug used to treat Parkinson’s disease (L-DOPA-induced dyskinesia). Dyskinesia, which is treated in the field of psychiatry, is caused by long-term use of antipsychotic drugs (tardive dyskinesia). Neither of these symptoms occurs immediately after taking the medication (from the same day to several days), but rather occurs several months to several years after starting the medication. In L-DOPA-induced dyskinesia, the body jerks and moves involuntarily. Tardive dyskinesia causes the mouth to move. In order to elucidate the mechanism behind the occurrence of side effects that occur after long-term use of therapeutic drugs, one method is to follow the known effects of the therapeutic drugs one by one. Since it can be seen in a few seconds, it is not realistic to track the accumulation of pharmacological effects in seconds until a month later.
In this study, we focused on changes in brain structure associated with learning. In this previous study (Reference 1), humans who were unable to carry a bean bag at all were trained until they were able to do so. When learning to play beanbags, it takes a lot of trial and error until you finally get the hang of it. There are countless steps, but if you just cut down to the results, you’ll see that you can now make a bean bag. Brain structure images are taken using MRI (Note 1) when the child is unable to wear a bean bag, and MRI images are also taken after the child is able to wear a bean bag. As expected, we found that there were differences in brain structure before and after. We ignore the various reactions that occur in the brain during the learning process, and attribute the difference between being able to do something and not being able to do it to differences in brain structure. Research using humans has come so far, but if we use model animals, we should be able to understand even more micro-level differences in brain structure. In this way, we attempted to elucidate the onset mechanism of dyskinesia using an approach that captures changes in brain shape.
Overexpression of the VGAT gene in striatal neurons is a common pathology in L-DOPA-induced dyskinesia and tardive dyskinesia.
First, this research group created mice with Parkinson’s disease in only half of their bodies (mice in which dopamine nerves were removed from one side). When these mice are given L-DOPA for 2 weeks, dyskinesia occurs only on the diseased side. When comparing the brain structures of the diseased and healthy sides using MRI, it was found that areas called the globus pallidus and substantia nigra become larger on the diseased side after the onset of dyskinesia.
Next, we used a micro- and nano-level histological analysis to find out whether the globus pallidus and substantia nigra of L-DOPA-induced dyskinesia model mice become enlarged due to the enlargement of the protrusions of which cells in the brain. We did the analysis. As a result, in the L-DOPA-induced dyskinesia model, the terminals of nerve fibers (axons of striatal neurons) that enter the globus pallidus become enlarged, and the neuronal cell bodies that receive input in the globus pallidus become enlarged. We found that it enlarged (Figure 1). Hypertrophy of axon terminals was correlated with increased expression of the VGAT gene (Note 2) in striatal neurons. Furthermore, this morphological and gene expression changes were also common in tardive dyskinesia.
In order to mimic the pathology that occurs in dyskinesia, namely increased VGAT gene expression in striatal neurons, we conducted an experiment in which the VGAT gene was artificially overexpressed in striatal neurons of wild-type mice. . As a result, the axon terminals of striatal neurons enlarge, the connected globus pallidus neuron cell bodies also enlarge, and neurotransmission between striatal neurons and globus pallidus neurons increases. I understand that. In both the L-DOPA-induced dyskinesia model and the tardive dyskinesia model, we revealed that overexpression of the VGAT gene worsened dyskinesia, and that knocking down the VGAT gene alleviated dyskinesia. These results make it clear that overexpression of the VGAT gene in striatal neurons is a common factor in the development of dyskinesia.
Based on the idea that the difference between the presence and absence of dyskinesia pathology is supported by differences in brain structure, we used model mice to develop macroscopic anatomy and microscopic histology, and investigated the genetic mechanisms involved in the onset of dyskinesia. This is a good example of how we were able to solve the problem.
Why does overexpression of the VGAT gene occur?
Under what conditions does VGAT expression in striatal neurons increase and dyskinesia develop? The research group developed a “Two-Hit Hypothesis” for the onset of dyskinesia and verified it.
In the case of L-DOPA-induced dyskinesia (Figure 2B): Dopamine neurons are lost due to Parkinson’s disease, dopamine concentration decreases, and signals mediated by dopamine receptor type 2 (D2R signal) in striatal neurons decrease. (1st hit). In addition to this, periodic fluctuations in dopamine concentration in the brain due to L-DOPA intake (2nd hit) cause dyskinesia.
In tardive dyskinesia (Figure 2C): D2R is blocked by antipsychotic administration (1st hit). Furthermore, various daily stimuli (emotional changes such as being surprised or happy, mental stress, illegal drug use, etc.) cause repeated fluctuations in dopamine concentration in the brain, which acts as a second hit.
In this paper, we will omit the details of the hypothesis testing method and results, but it is based on a state in which the D2R signal of striatal neurons decreases (1st hit), and fluctuations in brain dopamine concentration persist for a long time ( 2nd hit), it has become clear that VGAT is overexpressed in striatal neurons, leading to the development of dyskinesia.
Future outlook
This study discovered overexpression of striatal nerve VGAT as a common pathological condition of L-DOPA-induced dyskinesia and tardive dyskinesia, and it is expected that new therapeutic and diagnostic methods targeting VGAT molecules will be developed. Masu. Furthermore, the Two-Hit Hypothesis proposes a model in which predisposing factors (1st hit) and environmental factors (2nd hit) accumulate to develop into onset. The interaction between predisposition and environmental factors is assumed to be the underlying mechanism underlying the onset of many chronic mental illnesses, including schizophrenia, but it is unclear how each factor interacts specifically. I didn’t know much about it. This disease onset model successfully captures how the disease develops through the accumulation of environmental factors. I hope that this research will advance our understanding of the developmental process of mental illnesses.
