I have a question that I'm hoping some kind, knowledgeable person can answer. My dear uncle has been diagnosed with ALS and I'm struggling to fully understand this disease. Then again, aren't we all?

My question is this:

Why does ALS only affect motor neurons instead of both motor and sensory neurons?

My understanding of the brain and spinal cord is that motor and sensory nerves tend to run very close together. It seems that whatever causes motor neuron death would also cause widespread sensory neuron death unless there is a very big fundamental difference in the physiology of motor and sensory neurons.

I understand that misfolded proteins, dysfunctional astrocytes and reactive oxygen species (among other things) are suspected to play a role in ALS. However, it seems as though these things would not be selective for a motor neuron over a sensory neuron.

Does anyone know enough about the physiology of the nervous system to take a stab at this one? It has been bugging me for weeks. I'm Biology literate and good with a dictionary and Google, so please don't hold back.

Thanks,

Brittany

There are also many who claimed to have solved ALS or know how to stop it, even on this forum. Dot let those pretty words fool you. eat fat stay cool is probably the best you can do. Keep fingers x'ed for Brainstorm and Neuralstem. The gene puzzle, glutamate, inflammation, deficiencies or heavy metal theories wont lead to anything valuable for decades.

Sick cells need new/supporting ones, whatever the cause would turn out

Hi

Here's some stuff from the MNDA about possible reasons why motor neurones die.....

http://www.mndassociation.org/research/what_causes_mnd/what_causes_motor_neurones_to_die/index.html

......., I suppose there is no reason for other bits of the body to be targeted if a genetic curse has arranged some sort of preordained death for motor neurones alone?

D.

Brittany,
I have posted a theoretical answer to your question, (everybody’s answer is theoretical), in the “Forums Choice Program at ALS TDI” section of this forum, under the heading of “Possible sporadic ALS/MND treatment statagies”. There is more background information there that helps back up this answer. Link

Your question: Why does ALS only affect motor neurons instead of both motor and sensory neurons?

You have asked, what makes ALS..ALS? Why does it select motor neurons only? There are two “essential” things involved in every type of ALS: skeletal muscles, and motor neurons that connect to those skeletal muscles.

I am proposing that familial ALS is caused by the death of the motor neuron (which can be caused in many different ways via a mutation), which is followed by the disablement of the connected skeletal muscle which no longer receives any instructions from the neuron.

In sporadic ALS this is reversed. A compromised skeletal muscle stuck in a “chronic” first phase of cellular regeneration, repels the axon causing it to retract from the neuromuscular junction. The neuron can no longer transmit messages to the skeletal muscle so the body eventually eliminates the non performing neuron.

ALS does not select motor neurons; the failure of cellular regeneration in skeletal muscle or motor neurons cause the symptoms of ALS. The chronic failure of involuntary muscle, or smooth muscle, or neurons not connected to skeletal muscle, or sensory neurons, cannot cause any version of ALS. They can of course be the cause of, or be involved in other diseases.

Note: Edited the word dying with the word compromised.

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David Hicks.

ALS is a die-back neuropathy where the earlliest signs of the pathological process has been identified in the neuromuscular junctions. It is the largest NMJs innervating the very fast Type IIb (testosterone driven, typically male) muscles that are most vulnerable, while conversely, it is the smallest NMJs of the slow (typically female) muscles that are most resilient to the ALS pathology.

Furthermore and on a more detailed molecular level, it is a mitochondrial dysfunction with a concurrent energy deficit and protein misfolding that are the earliest pathological evidences. This is indicative of that the neurons are loosing the ability to sustain (cellular) life in their most distal parts.

I could gzo into more detail, but I doubt that it would add more to the current thread.

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Don't just ask what scientists can do to speed up the solution for ALS or when they will do it, instead ask yourself what you can do right now to solve ALS asap.

Spider,

On reflection, the wording "dying skeletal muscle" is too strong. A "compromised skeletal muscle" would be more appropriate. [I will edit the wording above.]

At the very start of ALS, (before symptoms), there is nothing wrong with the muscle. Over time the muscle slowly succumbs to wasting.

I believe that stem cell treatment will only benefit sALS patients; my personal view. If you do not stop the original cause (mutation) in fALS you would still have to be re-treated every few years.

If you consider a well progressed sALS patient that did grow new neurons from stem cell therapy, it is likely that it would take over a year for an axon to reach the calf of the leg. Once there, it would be repelled at the NMJ unless you had some other treatment to stop the original cause. The stem cells may help with respiration, talking, swallowing, etc. I don't know.

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David Hicks.

Brittany,

The G1/S phase of the cell cycle is only a preliminary phase of cellular repair. The cell must go through the G2/M phase to finish the repair or replacement. One of my discoveries is that during the G1 phase, proteins will fold to serine residues, (not threonine). This is a normal process and works normally during acute cellular regeneration. In sALS, regeneration is stuck in the G1 phase and has all the same settings as acute regeneration, the only difference is how long the settings last. Without apoptosis, time allows DNA faults to occur.

I say there is no misfolded proteins, only serine folding, which currently researchers do not understand.

In the G2 phase, apoptosis does not kill so-called misfolded proteins, it only eliminates cells with mutated DNA or some real defect. Folding to serine will stop as soon as the G1 phase is stopped. Simply entering the G2 phase will stop misfolded proteins. If the cells have been stuck in the G1 phase for a long time they would have produced some cells with faulty DNA. If you can push them into G2 phase they will be eliminated by apoptosis.

It is not the lack of apoptosis in the G1 phase that creates sALS, it is all of the changes that occur during the G1 phase when it is chronic. When you go through all the changes and settings you can see why ALS occurs.

Regeneration autophagy is just a part of the settings required to achieve G1 cellular regeneration (first phase). This type of autophagy is used to evaluate the condition and the type of cell involved. Although the cell is engulfed by an antigen presenting cell (APC), it is not intended as a killing machine like apoptosis. The APC engulfs healthy and compromised cells alike. Think of it as a quality control mechanism.

The G0 stage of the cell cycle is the quiescent condition, and it doesn’t produce the settings that the G1 phase does. The chronic suspension of cells in the G1 phase causes the disease. A half finished cake does not look like, taste, feel, or smell like a finished cake. So, what suspends a cell in G1? A chronic skeletal muscle injury, neuron injury, mutation (for fALS), virus, toxin, irradiation, in fact anything that will stall G1 in the appropriate cell and lineage. This is why there can be multiple causes.

On a side note, I do not have ALS, but I have started to use Soy milk on my cereal every morning.
A warning note! Hormones can cause unwanted effects with both high and low levels. Levels in the normal range is what is wanted.

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David Hicks.

I've just started reading up on ALS, and my bio+chem knowledge is non-existent, so please take this all with a big grain of salt as I may be misunderstanding and making many flawed inferences.

Please refer to PNAS 1006869107 "Deficits in Axonal Transport precede ALS symptoms in vivo" (go to www.pnas.org, and type in 1006869107 in the search box and download the PDF)

Their finding was that as ALS progresses, retrograde axonal transport also progressively slows down. HOWEVER, sensory neurons behave differently and do not show the same slowdown in transport regardless of the progression of the disease.

If I understand David's hypothesis correctly, he believes that compromised muscles fibers repel motor neurons causing them to retract from the NMJ thereby causing a disconnect in the signaling. Once the body realizes that it can no longer transmit messages to the muscle, it eventually eliminates the neuron.

My hypothesis is that it's actually the opposite. For some unknown reason there is a progressive slowdown in retrograde axonal transport as shown in the paper noted above. This eventually leads to degeneration of the soma from lack of neurotrophic uptake (see references 2-4 from the paper above). Once the neuron dies, the muscle at the other end naturally atrophies from lack of signaling.

The reason we don't see the same effect in sensory neurons is that this retrograde transport along the axon is largely unaffected as noted in the paper above.

We can take this thought process one step further. What if the deterioration of axonal transport is caused by mitochondrial dysfunction as referenced in the paper above? What if this mitochondrial dysfunction is caused by oxidative stress + glutamate toxicity? Obviously this begs the question of what then causes the increased glutamate etc?


I've also been thinking about the effects of chlorite ions and their effect of changing the state of microglia cells back to phagocytic. One of the things that we seem to observe (see Rob's graph overlaying a number of NP001 participants) is that when coming off sodium-chlorite treatment, their rate of ALSFRS-R progression increases and is a much steeper slope than pre-treatment. We don't have enough data to know whether this deterioration continues at the same rate or eventually goes back to the pre-treatment rate. I have a hypothesis for why we might be observing this:

1) Something causes a progressive slowdown in retrograde axonal transport
2) Soma slowly degenerates as neurotrophic factors slow down due to progressively slower transport
3) Microglia in the central nervous system (CNS) sense the damaged/unhealthy neuron and try to kill it
4) Patient takes in sodium chlorite. This is eventually uptaken into the motor neurons axon and makes it back into the CNS
5) These chlorite ions cause the microglia in the CNS to change state back to phagocytic and stop attacking the damaged neuron
6) The root cause of the disease however is not stopped and axonal transport continues to slow down, and the neuron continues to deteriorate at the original rate
7) When person comes off of chlorite treatment, the microglia change state and quickly kills off the most damaged neurons

I'm hypothesizing that this process is what causes the rapid decline post-treatment. HOWEVER, I would expect that the underlying rate of deterioration in axonal transport does not change, and so the rate of ALSFRS-R progression will go back to the original slope at the point that the two intersect.

Presumably even in the deteriorated state, the neuron is still able to convey electrical signals forward so we see a stabilization in the patients condition. However, if the chlorite is simply pushing off the inevitable, eventually we would expect to see progressive decline even if the patient remains on SC as the neurons die from lack of neurotrophic uptake. The chlorite would prevent the microglia from killing the neuron, but eventually they would just starve and die on their own.

I'm really sorry -- I know this is not what people want to hear, but it's one possible explanation for what we're seeing. I TRULY hope that I'm completely wrong on this hypothesis and that chlorite provides real and long lasting stabilization of motor neurons.

Ok, so taking the devil's advocate point of view:

If chlorite ions or hyper-oxygenation or something else triggered by the chlorite is what causes the reversal in the microphages, we would expect to see a slowdown or possible stabilization as neurons are not killed off. HOWEVER, it would not explain reversals or gains in function. We have MANY clear examples on this forum of people who have taken NP001/WF10/OSC and have seen regained functionality, often within a few hours or days. How could this be possible?

The only way for it to be possible if there were neurons (possibly with damage) that were in a "blocked" state, and the chlorite caused them to become active again. Obviously motor neurons that have died completely cannot be reactivated, which is why we only see some limited functionality return but not full functionality. The hope would be that if the neurons were no longer dying en masse, we could potentially see return of functionality to muscle fibers through collateral innervation from neighboring neurons (but I assume that would be on the order of months)

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