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The following was posted by Dave J on the als.net forum on Jan 12, 2015:

Lower Motor Neurons
Lower motor neurons (LMN's) respond to stimuli from spinal ganglia, have long axons, and activate the neuromuscular junction (NMJ) (also known as the motor end plate), triggering muscle contraction. There is a body of evidence to suggest that development of ALS disease symptoms is driven by withdrawal of the LMN from the NMJ, resulting in paralysis. When muscle fibers are no longer being activated, within a matter of a few weeks they deteriorate, resulting in muscle atrophy.

ALS LMN disease is focal; that is, it doesn't hit everywhere at once but starts in one or more places and spreads from those places. It is also distinguished from "glove and stocking" neuropathies which begin at the extremities on both sides of the body and then work upward. LMN disease which is not strictly speaking ALS may manifest symmetrically, for example "flail-arm disease". There are other LMN diseases that I don't know enough about to comment on, for example spinal muscular atrophy (SMA) and multifocal neuropathy. A glove-and-stocking presentation doesn't necessarily mean that the biological processes are fundamentally different from those in focal ALS: the G93a mouse (an animal model of human familial SOD-1 defect ALS) always presents as glove-and-stocking.

The focal aspect of ALS LMN disease provides important clues as to the nature of the disease. It spreads from one neuron to the next, almost as though it were an infectious disease process. One affected neuron withdraws from its motor end plate, the denervated muscle fibers (or motor end plate itself)thus affected release biochemical signals that they're available for hire, and an adjacent motor neuron that is still more or less healthy extends its neurites to the abandoned motor end plate and takes over the job the other neuron had given up on. The resulting arrangement where one neuron does the job of two or possibly more, is called a "giant motor unit" (GMU). A normal healthy person has some GMU's, especially if they've engaged in activities that caused them to get banged up a lot. In the case of ALS, it's typical for many GMU's to develop before the body runs out of LMN's healthy enough to perform the GMU maneuver. GMU's work surprisingly well for a while, leading to statements that (for instance) by the time you have symptoms, half your neurons are already dead and you've probably had ALS for years and didn't know it. I mostly disagree with such statements but it's easy enough for ALS spokespeople to think that's what the evidence points to.

Lower motor neuron disease, when the symptoms first emerge, usually progresses quickly. ALS according to the narrow El Escorial definition includes lower motor neuron disease manifested by muscle atrophy, and we've all heard the "spokesperson" statements that once you've been diagnosed, your life expectancy is 2-5 years and if you read the fine print, what they really mean is 2 years, they're just lifting the limbo stick for a few patients with long livers. The message to take home is that LMN disease typically progresses rapidly. What kills us is usually complications (for example pneumonia) resulting from respiratory failure.

Most motor neuron disease is of the ALS type, UMN and LMN. UMN disease by itself (so-called "Primary Lateral Sclerosis") is usually fairly slow. In typical ALS, the UMN disease is accelerated, it keeps up with the LMN disease. In Aketri's "ALS Theories Summary" thread and probably elsewhere, we've called into question what UMN disease actually is. In what follows next, I will offer one interpretation of why ALS is defined as LMN+UMN and neither LMN nor UMN alone will suffice. It's not the only possible interpretation.

AN EXPLANATION OF LOWER MOTOR NEURON DISEASE and its relationship to UMN disease in ALS.
This is a theory to explain most (not all) LMN disease associated with a formal diagnosis of ALS. I think it's a pretty good theory, but a smart brain could differ. I'm not waiting on a consensus theory from the ALS industry experts, that could take decades. I need a plausible theory NOW because I'm trying to put together a therapeutic regime that has a reasonable basis.

Something happens to stress a neuromuscular junction. It could be a mechanical injury, esp. a stretching injury. It could be a latent retroviral infection. It could be a genetic abnormality affecting the whole body, but one part of the body is going to fail first for its own peculiar reasons. ALS is many different diseases, we don't even know how many. What the pile of diseases has in common is LMN + UMN disease at the time of diagnosis, which happens months or years after the first symptoms and the first symptoms may come after years of ongoing damage that the patient didn't notice because of compensatory mechanisms esp. development of GMU's.

So let's start at the failure of the first neuromuscular junction, however that happened. One LMN is no longer connected to a NMJ. It will eventually figure out that it's useless and will release biochemicals that tell the immune system (in this case glial cells)to kill it so it can be gotten out of the way.

We also have an adjacent LMN that (surprisingly) is still healthy enough to actually sense an abandoned motor unit and commandeer it along with the one it's already got. Pretty soon (probably a couple weeks) what was two independent motor units is now one giant motor unit. The patient is unaware anything is wrong. Normal healthy people have GMU's that arose during childhood mismatching of muscle and neuron growth, and from injuries mostly in the "no biggie" category.

The neuron that is now doing double duty on the far end, will soon be doing double duty in the spinal ganglia as well, as the synapses of the ganglia rearrange to route commands to the detour rather than into a cul-de-sac. That double duty is usually lightweight work, but strenuous physical activity could stress the heck out of it. That's not good: it's now a prime candidate to be the next neuron to fail.

It fails.

Its GMU fails. Within weeks, the muscle fibers actuated by that GMU atrophy. In the process of atrophy, they release biochemical signals ("cytokines") to the immune system that something's going wrong. Meanwhile back at the ganglia, the same thing is happening: stuff isn't working right and the immune system smells it. Literally, just as an amoeba smells its next meal and crawls there with its pseudopods.

Gliosis has just set in. The immune system esp. on the brain & spine side of the blood-brain barrier (BBB) is not always very smart. The nervous system's glial cells see some sort of carnage going on and believe it's their job to go blow the problem to smithereens with glutamate (leading to oxidative and free radical damage) so the waste disposal system can digest the stuff into pieces small enough to get back through the BBB (or to find some useful way to recycle the raw materials). When the problem is infection, ideally the infectious agent is killed and the corpse is incinerated and dumped into the Red River for delivery to the kidneys. Almost anywhere else but in upper and lower motor neurons, this works. The problem is that the body has no way to replace upper or lower motor neurons. In an adult, starting from scratch a stem cell would need military-grade global positioning to know where it was supposed to start and finish. Sorry, it ain't got GPS. Development of spinal (upper and lower) neurons is something that happens in embryonic development when the progenitor cells have associated bone and muscle tissue development to coordinate with. Salamanders can regenerate LMN's, but only if they're generating the whole limb from scratch meanwhile.

Glial cells are trying to kill off an infectious agent, but what's being killed is motor neurons. As they're dying, they release caspases that scream to the immune system "Help! something's killing us! Bring on the heavy artillery!" When LMN's begin dying, you've got a full-blown neurodegenerative cascade going on, and it will continue until there are so few motor neurons left to die that the immune system thinks it's finally fixed the problem.

So about those upper motor neurons? They're overstressed because of inflammatory cytokines circulating in the system, and overstressed because they can't figure out what to do to make stuff work right. They're mostly overstressed at the spinal ganglia where messages from upstairs (UMN's) and downstairs (sensory neurons involved in reflex arcs) are coordinated. Like I told my first (quack) neurologist, no I'm not in pain, I'm grimacing because of the mental effort it takes to make the damn legs do anything.

.......That's a fairly elaborate and specific theory. How much explanatory power does it have? The explanatory power doesn't prove the theory correct, but at least it's something that can be pitted against other theories or no theory.

I've already explained lots of stuff this theory explains, for example the focal nature of ALS and its development into a devastating loss of motor neurons. It explains why among the MND's, ALS is the most common. It explains why a whole slew of different actual disease causes, can lead to a similar clinical presentation.

It also explains why the most common single anecdote among ALS patients is "a year ago I was running marathons, WTF happened?" and why that phenotype are (as far as I can tell) almost always LMN-dominant and fast progressors. There's been a lot of speculation whether the genetic predisposition to extreme sports carries a genetic risk of ALS, or if it's the extreme sports activities that lead to the risk. There's some evidence to support the theory of genetic predisposition, but that theory doesn't preclude my alternative and may in fact amount to the same thing.

WHAT'S THIS SUGGEST IN TERMS OF THERAPEUTICS?

1. It suggests that neurological anti-inflammatories are necessary. Fortunately we know ones that have pretty good science to substantiate them-- ibuprofen, and curcumin. And fortunately, these do not work the same way, meaning that it makes sense to combine them.

2. It suggests that when it comes to effective therapeutics, there's a critical time window: once the neurodegenerative cascade is well underway, stopping it is going to be almost impossible.

3. It reinforces the importance of preserving muscle tissue, since the biochemicals released by disintegration of muscle tissue upregulate an immune system already gone awry. Therefore take advantage of moderate exercise, adequate protein intake, neuromuscular massage, and/or electrical muscle stimulation. The old-fashioned thinking was preserve the muscle for its own sake, but the new theory is preserve the muscle in order to stand a chance of halting the neurodegenerative cascade.

4. It reinforces the importance of preserving the neuromuscular junction. In the context of ALS, that means combining three things: zinc, trimethylglycine, and ethyl alcohol.

5. It reinforces the importance of antiglutamate therapy, since glutamate is the #1 toxic substance involved in killing off lower motor neurons. There are many different pathways of antiglutamante therapy. The good news is that there's gobs of stuff available to throw at those pathways, and the bad news is that we don't really know yet which of those pathways are most profitable to throw the monkey wrench at.

6. It points to the critical role played by axons. Axons are to motor neuron disease what Napoleon's and Hitler's supply lines to the eastern front were: the highway that made the long distance conquest possible, and the vulnerability that killed both imperial dreams. We folks here usually don't pay much attention to multiple sclerosis (MS) [a group of axon degenerative diseases] therapeutics, but once we've licked the problems at the NMJ the axons are going to look like very attractive therapeutic targets.

 

UPPER MOTOR NEURONS

 The UMN's have long axons because they travel down the spine to ganglia where their actions are coordinated with other motor and sensory neurons.

About 95% of research on UMN's in relation to ALS has to be deeply mistrusted, because that 95% is based on the coaxial and repeater synapse model which is objectively false, and it also ignores all the complicated stuff that happens to electrical communication as it passes through the mid and lower brain structures. Like for instance where Parkinson's happens-- sometimes in ALS. The industry standard UMN-LMN model is either worthless or nearly so.

So let's start out from scratch and see where it leads us.

UMN's don't begin at ganglia and don't terminate at NMJ's. We're told they begin in the motor cortex, which might be something like spinal ganglia; and that they terminate at the spinal ganglia which might be something like NMJ's. I've learned to distrust darn near everything in print regarding UMN's. What's the next step?

1. Primary Lateral Sclerosis is on a continuum with upper motor neuron dominant ALS. Both diagnoses are associated with much longer survival than with "regular" ALS.

2. This strongly suggests that PLS/UMND-ALS is not driven by an apoptotic cascade. It doesn't cause the death of muscle tissue and more importantly doesn't cause the death of nervous tissue at such a rate that a reactive gliosis driven cascade issues a summons to the local cemetery anytime soon. That's driven by LS/MFT (sorry, couldn't resist....)

3. The glutamate problem seen in LMN disease is mostly a reactive gliosis problem. [u]UMN disease isn't a neurodegenerative cascade in the same sense that LMN usually is.[/u]UMN disease is either driven by concomitant LMN disease (as described a few paragraphs above), or is driven by factors that don't drive LMN disease.

 

BULBAR

These are nerves that don't go through spinal ganglia. They originate in the brain and go to muscles in the face and neck, especially muscles relating to speech and swallowing. They coordinate with sensory neurons but I haven't seen that mapped.

Bulbar neurons are like NMN's in that they have NMJ targets, and like UMN's in that they don't have NMN it.