Dopamine modifying agents

[Amw66]

I found the early symptoms of Parkinson's, which, as far as I understood, is a dysregulation of MSNs through a lack of Dopamine resonates with MECFS symptoms quite well.

But of course these symptoms are unspecific and could be caused by a lot of mechanisms.

My father in law had Lewy Boy dementia which shares some symptoms with Parkinsons - his death certificate is a mish mash citing both. There were many similarities to symptoms my daughter has with ME. He was surprised that I could understand and empathize with his symptoms.

 

[Amw66]

My daughter seems to have issues with glucoronidation ( from previous reactions to drugs / substances) - might give a hint for dopamine issues.?

 

[Utsikt]

Let us propose that ME/CFS is due to a long term failure of function of eccentric medium spiny neurons in certain sites. Perhaps these neurons have suffered an epigenetic change that makes them unreponsive to certain stimuli. Perhaps that involves a loss of the machinery for maintaining dopamine or glutamate mediated interactions at either dendritic inputs or axonal outputs. Basically the cells become deaf to the relevant transmitter. If you then give drugs that raise or lower levels of the relevant transmitter then you might not see any effect.

This popped up in the news recently: some neurologists got an award in Norway for their work that demonstrated that the dendrites and axons synthesise their own proteins independent of the main body of the neurons. This might be olds news to you because they’ve been at it for decades, but it opens up new angles.

Perhaps ME/CFS is related to this process being messed up in certain neurons? It would still have to be maintained something external to the neuron, but it might mean that we have to look inside the neurons instead of at the receptors on the outside.

 

[Violeta]

This popped up in the news recently: some neurologists got an award in Norway for their work that demonstrated that the dendrites and axons synthesise their own proteins independent of the main body of the neurons. This might be olds news to you because they’ve been at it for decades, but it opens up new angles.

Perhaps ME/CFS is related to this process being messed up in certain neurons? It would still have to be maintained something external to the neuron, but it might mean that we have to look inside the neurons instead of at the receptors on the outside.

Maybe one of the sources in this list would have some information you might find helpful.

That list is from this study.

https://www.ias.ac.in/article/fulltext/jbsc/006/04/0569-0583

 

[ScoutB]

I am more puzzled by why eMSN should fall prey to some post-infective error in maybe less than 1% of people in a lifetime.

Unlikely to be closely related, but an example to chew on could be why only certain neurons are affected in Parkinson's disease, because some effort has already been put into figuring that one out.

Calcium, mitochondrial dysfunction and slowing the progression of Parkinson’s disease (edited for brevity):

What factors might contribute to pathology? One approach to this question is to look at the properties of vulnerable neurons to determine if they have common features that might be affected by risk-factors associated with Parkinson’s: age, exposure to environmental toxins and a collection of genetic mutations (Surmeier et al., 2017). Indeed, many of the neurons that are most profoundly affected in Parkinson’s have a loosely connected functional role in the brain. They are principal neurons in neuromodulatory control networks, contrasting them with neurons in brain networks responsible for epicritic sensation and precise motor control.

[...] it appears that these neurons share a number of traits that might put them at-risk. The most notable and best characterized of these is a long and highly branched axon with a large number of transmitter release sites. This diffuse axonal arbor helps these neurons coordinate the activity in large networks, like the basal ganglia or the spinal cord. For example, SNc DA neurons in the rodent have axons that branch profusely in the striatum and possess as many as 200,000 vesicular release sites (Matsuda et al., 2009).

(I wonder how eMSN compare to this?)

Although less well characterized, neurons in the DMV, GCN, RN, LC, PPN, BFN, LH and ILN all share this feature (large, diffuse axonal projections) to varying degrees, distinguishing them from the vast majority of sensory or motor neurons in the brain, which typically have spatially focused, modestly branched axons that conform to topographic maps. Why might a long and highly branched axon increase vulnerability? There are several theories that have been proposed (Bolam and Pissadaki, 2012; Hunn et al., 2015; Pacelli et al., 2015). But, not all neurons with long, branched axons are vulnerable in Parkinson’s (e.g., striatal cholinergic interneurons), suggesting that some other factor is in play.

Another shared feature of at-risk neurons appears to be their distinctive physiology. In vivo, at-risk neurons that have been studied have slow tonic activity. The best studied member of this class is the SNc DA neuron. The action potential of these neurons is slow and broad, which maximizes Ca2+ entry and promotes slow rhythmic activity. The slow, rhythmic activity (2–10 Hz) in these neurons is autonomously generated and accompanied by slow oscillations in intracellular Ca2+ concentration that are triggered by the opening of plasma membrane Cav1 (Cav1.2, Cav1.3) Ca2+ channels and release of Ca2+ from intracellular, endoplasmic reticulum (ER) stores.

Once in the cytoplasm, Ca2+ is relatively free to interact with other proteins as the abundance of Ca2+ buffering proteins, like calbindin, is low. This combination of features – broad spikes, pacemaking, low intrinsic Ca2+ buffering and cytosolic Ca2+ oscillations – (not any one) is what distinguishes SNc DA neurons. For example, VTA DA neurons, which are significantly less vulnerable than SNc DA neurons, are autonomous pacemakers with broad spikes, but have smaller Cav1 channel currents and strong intrinsic Ca2+ buffering.

They go on to discuss various problems sustained elevations in cytosolic Ca2+ could be causing, e.g. overproduction of ROS and mitochondrial issues. I've also seen interference with mitochondrial metabolism listed as the cause of damage in MPTP poisoning (which affects the same neurons as Parkinson's) but haven't looked into it much yet.