How MPTP can precisely effect only dopaminergic (DA) neurons in substantia nigra while creating mice model of Parkinson's disease, and not DA neurons in other areas of the brain ?
Hi,
I'm not an expert of the topic but I guess that due to their high content in dopamine, dopaminergic neurons are more sensitive to oxydative stress which is a main way of action of MPTP.
Thank Julien...but my question was, why only dopaminergic neurons of nigra, why not dopaminergic neurons in other areas.?
This is the billion dollar question...as I understand it these are the only DAergic cells that also express neuromelanin (at least in primates). Another thing to consider is DA transporters - expression profiles might be different between neuronal populations. Also- are you absolutely certain it's the ONLY region affected? Rather than simply being the most often considered due to its link to Parkinson's disease research? Has anyone looked at global brain degeneration in the MPTP models?
Thanks John...Ya, MPTP mice model is the most used neurotoxic model because it brings specific degeneration in SNpc DAegic neurons, which mimics PD. Ya, there are studies where they have looked into other areas of the brain. Neuronal death, especially DA neuronal death is negligible in other parts. As you rightly mentioned, DAT place an important role. I also came across a study mentioning the role played by VMAT-2 receptors. They say it's the ratio of DAT and VMAT-2 that decides the susceptibility of DA neurons to MPTP. I don't think neuromelanin has got any direct role in MPTP susceptibility in primate models.
Hello
MPTP selectively destroys dopaminergic neurons within the SNpc (espcially melanin-containing neurons) because its metabolite MPP+ (very actif), binds with high affinity to neuromelanin. MPP+ bound intracellularly to neuromelanin may be released very slowely, resulting in damage to the neurons of the substantia nigra.
Thanks Omar...that's new for me..that might be true in primate models..but what about mouse model which doesn't have neuromelanin in their DA neurons..
In mouse model it's preferable to use the 6-OHDA neurotoxine than MPTP, and whene you talk about "model" this mean that you can choose the site of the injection "in situ" using the Stereotaxic coordinates of rats brain (Watson & Paxinos), so like this you can administer the neurotoxine within the SNpc specifically.
Please check out the review and reference attached that asks why SNpc neurons die but VTA neurons dont
Neuromelanin has the curious property of binding certain chemical agents very tightly. Unfortunately, MPTP, or at least MPP+ (or probably both) is among these, as is 6-hydroxy dopamine. My hypothesis is that the melanin has a normal function to bind and store dopamine itself. If it can re-release stored dopamine, the melanin packet could supplant the function of dopaminergic vesicles to release synaptic dopamine and serve as a muscle memory system. I have a publication under review addressing some of these topics and am keen to discuss them further.
Are microtubules involved in the pathogenesis of PD? I ask this question because these structures are main participants in the correct functioning of neurons
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