Notes on Parkinsons Disease and Neurodegeneration
I was asked by someone on Reddit whether there was any way he could avoid developing Parkinsons Disease, even with it being in his genetics and family history; so I went on a quest to find out.
I write a lot about Dopamine and Dopamine-related subjects on Reddit and elsewhere (not here yet… its coming). I love to try and help answer questions, help to explain the myths (like “dopamine is a happiness chemical”, it is nothing of the sort). Sometimes, people see my writing and send me DMs with questions that are particularly close to their home. One of those was a question I received from someone who has a genetic predisposition to developing Parkinsons disease, and just wanted to know whether there was any way he could avoid or prevent it. I decided he deserved the best answer I could possibly give, and so I spent several days engrossed in pubmed literature specifically on this topic and wrote back an essay which I’m actually quite proud of. Honestly, I’m certain there must be inaccuracies and misconceptions in what I’ve written, but on the whole, I believe it to be correct in its essentials.
IMPORTANT NOTE: This is not medical advice of any kind, and you should not treat it as such. The fact is that I am not a neurologist, or a doctor, I’m just some internet person, and if you are seeking advice especially on neurological conditions that might affect you or your loved ones, I urge you to see a qualified specialist.
So with that out of the way, here’s what I wrote:
Response
A lot of what I know might be relevant if you ever develop symptoms, but Parkinsons is effectively a kind of accumulation of misfolded proteins in areas like the Substantia Nigra. I don't know how much you already know about the brain, so I'll try to explain things as I go.
So, Parkinsons belongs to a group of diseases known as the Synucleinopathies. This refers to neurodegenerative diseases which involve abnormal buildups of clumps of a type of protein called alpha-synuclein (hence the Synucleinopathy name). This protein is pretty important. As you likely already know, the connection between 2 neurons - called the synapse - involves a transfer of neurotransmitters between the pre-synaptic neuron (sender) and post-synaptic neuron (receiver). These neurotransmitters reside inside containers called "vesicles", which are inner bubble-like structures residing inside the neuron cell that hold a certain quantity of neurotransmitters. The neurotransmitters are transported into and out of the terminals with the help of Alpha-Synuclein (which we'll call AS from here).
When an electrical signal reaches the axon terminal, one or more vesicles attach to the membrane wall of the neuron and release the neurotransmitter into the synapse. However, without AS, neurotransmitters simply won't go anywhere. It all stays in its vesicle, or in "cytosol" space. What I understand to be happening is effectively that the neuron doesn't realise any of this, and keeps working to build up its quantities of neurotransmitter each time a signal is supposed to have been released. At some point, your neuron simply has too much neurotransmitter. This seems to lead to the death of the neuron, particularly dopaminergic neurons for some reason. Whether this happens because the neuron breaks apart from over-filling, or blocks the flow of other important chemical factors through the cell, I'm not sure.
Genetics
In Genetic PD, the problem is in the way that AS is encoded in the genes. The AS gene is 140 characters (or base-pairs) long. There is a mutation in there that happens which causes AS to be manufactured incorrectly, into a misfolded shape. This means that not only does it no longer function as it is supposed to, they can also get stuck together and build up into chunks called "Lewy bodies", which itself can cause catastrophic damage to their neurons. This is kiiinda similar to how in Alzheimers, there is build-up of beta-amyloid "plaques", which can strangle neuronal connections, but this happens mostly in the cortex, the upper layer of brain matter.
This particular dopaminergic-focussed impact is clearly demonstrated in the symptomatology of PD, which is primarily in the areas of motor control, activation and decision making, reward and reward-based reenforcement learning, attention and motivation. All of that comes from the Basal Ganglia, the true Imperator of Dopamine. The vast majority of dopaminergic neurons are focussed in this small, mid-brain structure. So PD has most of its impact there.
To be continued after this short break:
Part 2: Electrochemical Voodooloo.
So, like I said, Alpha-Synuclein (AS) is fairly darn important stuff. The sad thing about it is that I just don't know of anything specifically which could stop its genetic malformation. I felt really hesitant to write that because I’m certainly not saying it’s impossible by any means, I know there will be some way, some how, somewhere, and eventually medical science will find a way. There are some things in the works with regards to neurogenesis, which might be able to cause existing stem cells in the brain to produce replacements, but I don't know anything else about that at the moment. However, there are some potentially very early signs that might prompt one to seek early treatment.
Something that often happens to patients of the Synucleinopathies - well before they know they are in fact a patient - is acting out ones dreams. I don't mean just talking in your sleep or the occasional movement, I mean like sleepwalking but with more danger. Anyone you live with is gonna have a real interesting time. There was a brief period of my life where I would suddenly appear to wake up, scream at something to get away from me, and LEAP out of bed and across the room, where I'd slam myself against the door and hit the floor, or various other such things. The distance was a good 3 metres, and I'd wake up with sore knees.
Luckily for me, it was only temporary, and I haven't had such an episode like that in many many years. But with PD, that can sometimes be one of the earliest visible signs, many many years before diagnosis for some folks.
Here's where I'm gonna get into a bit of speculative connecting-of-dots, in order to try and synthesise the vast amounts of research and dense technical detail I've read up on into something that will hopefully seem coherent, but I will almost certainly be wrong on some or all of it, and will miss some important stuff I'm sure. With that in mind, here we go.
Lewy Bodies
Lewy bodies - these chunks of alpha-synuclein - begin forming in and around the brainstem/base of the brain. Some of those nerves are from the vagus complex, coming all the way from the gut, joined together to form the "vagus" nerve. The vagus extends all the way up to the base of the brain stem, into a structure called the Medulla Oblongata (just outside the blood-brain barrier), and then into the Ventral Tegmental Area (just inside the blood-brain barrier).
The Ventral Tegmental Area (VTA) sits right at the very base of the brain, inside the blood-brain barrier, and has connections directly to most of the dopaminergic structures of the Basal Ganglia (BG), like the nuleus accumbens. The thing about most dopaminergic neurons is that they can't manufacture their own dopamine. They typically need to obtain it from elsewhere. This is where the VTA comes in, as it *is* equipped with its own dopamine-manufacturing machinery, and since it is directly connected to much of the BG structures, it offers expedited express shipping and factory-floor-to-door delivery. So the various complex structures of the BG - handling all sorts of tasks for motor movement, memory recall, action selection, attention, etc - rely on this regular supply of dopamine coming from the VTA factory and occasionally elsewhere. Without it, well, those neurons can no longer communicate, and everything comes to a halt.
So as these Lewy bodies form, one place they really like to hang out is the VTA. In their early phase - which can take many years, or a matter of months - once they are in the VTA is when you begin experiencing some troubles with motor movement, with concentration, motivation. It's real subtle at first and for a while. Sometimes it even gets misdiagnosed as ADHD or similar conditions, since it looks and quacks like ADHD. But very slowly things get more and more difficult to control. The reason is because as the lewy bodies build up in the VTA, we're losing the vast majority of our ability to create dopamine for our motor cortex and mesolimbic pathways to use, and so we lose the ability to transmit signals in those areas of the brain.
Effects on Motor Control
In the motor cortex, by default *everything* is trying to move, all the time, constantly. The reason you're not flailing wildly 24/7 is because the Basal Ganglia (BG) maintains a series of gates, which are controlled very finely, to allow only chosen signals to pass. So, for example, lift your right arm. Notice how your left arm is still? Same with your legs probably. Now, on that right arm, move just your pinky finger up and down. See how fine-grained that control is. The basal ganglia - this chunk of brain no larger than a plum - is so powerful, so finely tuned, allowing us to have the most fine-grained control over our bodies. Everything happening within the brain to realise those movements, from the signal to move, to the signal that controls the gates, is faciliated by dopaminergic neurons. When a neuron firing off a signal to move goes kaput, it might affect the abiity to move one small area, like a finger, but when the neurons controlling the gates go down, you can either have entire swathes of the body with no ability to move at all (if the gate remains shut), or you might be unable to stop them from moving (if the gate is kept open).
Now, when you sleep, these gates are designed to remain shut, preventing you from acting out your dreams. Should you start to run low on dopamine, or their control signals become damaged or destroyed due to these lewy body chunks, they're not gonna function properly, so those movement signals - normally blocked when asleep - might get through, and take you on crazy adventures in the night. Conversely, it might cause the opposite too sometimes, a stiffness known as "parkinsons gait". This is obviously because both systems - activation and inhibition - of motor control are dopaminergic.
Complicated :(
Hence why the main treatment that I know of - and only truly effective one - is dopamine supplimentation by way of metabolising L-DOPA, which is the precursor chemical to Dopamine. Basically, it’s a way of artificially replenishing your brains stock of Dopamine, which it can no longer produce on its own. Once it crosses the blood-brain barrier (full dopamine can't do that unfortunately) L-DOPA easily transforms into Dopamine, floods into extracellular space, where it gets picked up by VMAT and sucked in to the vesicle bubbles, ready to go, so your neurons can communicate again.
So I'm really sorry that I don't have a lot of great answers to your main question. I read so much literature to write this, looking for anything that might give some clues. The best I can offer is the hope that in the near future these neurogenerative treatments turn out to be capable of rebuilding the lost neurons. There are some statistical risk factors to avoid however. Avoid MPTP, an industrial neurotoxin. That shit is nasty. Try to minimise the amount of commercial pesticides you come into contact with or consume (that's a tough one, but it's a small risk factor). Also, especially important: avoid brain damage! Don't get into a fight with the ground, or any metal pole or moving metal object. Very important.
But more important than all of that, do what you feel you need to do to take care of you: mind, body, soul. Speak to a specialist Neurologist if you’re ever in doubt. When you think you might be seeing some symptoms, even if it turns out not to be, go get it checked out if you can. Remember, it might not even develop at all. I think the odds go to only about 15% when it runs in families. You've got the whole other 85% there.
Fin
Thank you for reading. If I’ve made any mistakes or got things wrong, please do let me know about it so I can correct it. Just remember to be nice.
If you ever have any questions or concerns, a qualified neurologist is the first port of call. However, I am always more than happy to answer questions of curiosity about the brain. If I can ever be of assistance, please let me know. I have enabled the Chat feature on substack as well. If you enjoyed this one, please leave a like, it really encourages me to keep writing when I know it’s useful to others.
Thank you for being part of this with me.
Dopamine supplementation is not the only treatment for Parkinson's. There is also deep brain stimulation, which has been remarkably effective in some patients, Apparently it's not suitable for all Parkinson's patients.
https://www.michaeljfox.org/deep-brain-stimulation#:~:text=Deep%20brain%20stimulation%20(DBS)%20is,DBS%20is%20not%20for%20everyone.