The above sentiment matches my theory 100%. My theory proposes that sALS is mainly caused when cellular regeneration becomes stalled in the first phase of regeneration. The first phase of regeneration is normally transient and protective when acute, but if the process becomes chronic, it becomes toxic. For example, apoptosis is down regulated during first phase regeneration. This is fine when the process lasts for a number of hours, but if it lasts for months or even years it becomes toxic. The settings remain exactly the same. I am presently writing a more detailed but still brief explanation of why and how this happens. It should be ready late this week. This will be posted under “Forum’s Choice Program at ALS TDI” under the topic “Possible Sporadic ALS/MND Treatment Strategies”.

I do however have reservations on the rest of the article; especially with the hope of forum members that blocking TGF-β may help with sALS. Whether the proposed treatment (losartan or ARBs) stops muscle regeneration is another matter.

Beta lineage cells (muscle cells) going through regeneration will express Decorin or Biglycan proteoglycans which both bind and inhibit TGF-β. If this is correct there will be no TGF-β expressed in the muscles of most sALS. From my investigations, IGF-2 is up regulated in sALS; not TGF-β; but either way, stopping either one for any length of time would cause too many side effects.

TGF-β is said to suppress the expression of c-myc, a gene involved in G1 cell cycle progression, and blocks the cyclin E:CDK2 complex, which then blocks retinoblastoma phosphorylation, which blocks the advance through the G1 phase of the cell cycle (Ref: Wikipedia-TGF-β). This effectively stalls the first phase of regeneration. My theory says this is already happening in sALS only it is caused in a different way.

If treatments from Ark Therapeutics Group plc. with ARBs or ACE inhibitors can force a first phase regeneration into second phase regeneration, it is probable that it would actually work equally as good on the IGF-2 pathway.

Ark has also proposed a possible chronic treatment using losartan to prevent age-related muscle loss. If the treatment does actually prevent the first phase (G1) of regeneration, any chronic administration is likely to prevent all beta/mesoderm lineage cells from regenerating. This would include all muscles and involve skeletal muscle, heart, tongue, etc., and also bone and teeth. This would cause more side effects than the original problem. Short bursts of treatment with breaks sufficient to allow cell regeneration may be helpful.

PS: The failure of the neuromuscular junction (NMJ) in sALS is caused by signals that cause the repulsion of the axon. These signals only occur during the first phase of regeneration. Muscle cells produced during this phase have no cross linking, and cell adhesion molecules are relaxed to enable cellular migration. When the skeletal muscle is in this state it does not want to receive orders from the neuron to heavily retract, as this will break apart the newly developing cell structure. For this reason the axon is repelled by the muscle to protect the cellular repair until it is strong enough. If this situation remains chronic, the neuron will think the muscle is no longer there, and the neuron will eventually die. This is not the case for fALS so it is no use testing this on the mSOD1 mouse. Familial ALS uses a different pathway.

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David Hicks.

This sure looks familiar, I believe we've seen Mr. Shapoval here before offering his theory. Whether he actually believes it himself or not, I don't know.

Failure of iron regulation may play a role in ALS. Remember IronJustice? He actually had a point or two.

However, Shapoval's theory comprises claims about magnetism. Claims which are inconsistent with biochemistry and magnetic physics, and for which he offers zero evidence. (The link he provides is to his opinion same as you see above, not related to the subject matter of the professional news article where he commented.)

I'm hard to BS about magnetics.

--Dave J.

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EDIT

Mr. Shapoval, you done been busted!

http://www.als.net/forum/yaf_postst47747_Move-over-Ironjustice-here-comes-Ironconception.aspx

Mr. Shapoval, if you think I'm a hard sell, try ENV.

--Dave J.

There's been a recent flurry of posts relating to oxidative stress being a provocateur of autophagy, including comment that perhaps this is one reason why antioxidant therapy hasn't produced much obvious success in ALS and perhaps has even been a risk factor.

So-- herewith, I propose another theory of what goes wrong in ALS for the legendary "Aketri's Thread". Sure miss that guy, but he left us an extraordinarily valuable legacy. His (this) thread may in time prove to be the single most useful individual contribution anyone ever made to the quest for successful ALS therapeutics.

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Okay, so we got this deal where some molecular pathways require oxidative stress to induce autophagy. It's one of those things one might not have the insight to predict, but once you've seen the reports it's easy enough to say "well gee, nobody who embraces evolution as the foundation of biology should find that surprising."

Also, it appears that in most ALS (perhaps all?) one of the phenomena observed is the aggregation of molecules which should not have aggregated, the said aggregation having been made possible by some combination of molecular errors. The errors may pertain to the individual molecules (for example genetic errors in SOD1 errors caused by reactive oxygen or metallic substitutions); or the errors may be part of a disease process involving other biochemicals which lowers the energy gap between the separate molecules and their aggregates driving an exothermic reaction that would otherwise not occur. (Note: heat itself lowers such an energy gap, hence the phrase "heat shock proteins".)

As it turns out, we don't have to look very hard to find heat shock protein inducers among dietary supplements. Good examples include turmeric (curcumin) and peony root (preferably boosted by licorice root).

Curcumin is a widely researched and well known anti-inflammatory, since it's a dietary staple item all the way from Mumbai to the mustard on a Coney Island hot dog.

I wonder to what extent natural anti-inflammatories rely for their action in part on promotion of autophagy.

The question cuts both ways. Peony root is not generally regarded as an anti-inflammatory, but is regarded as a first-class HSP inducer esp. in combination with licorice which itself is not generally regarded as either an anti-inflammatory or a HSP inducer.

Another way this "cuts across the grain" is that curcumin is also often regarded as an antioxidant, although it's not clear to me in what molecular antioxidant process it participates.

Also cutting across the grain, is the abundance of evidence of oxidative stress as a basic pathogenetic process in ALS, it's not like we need an IV infusion of nitric acid to cure ALS. But then there's chlorite therapies.....

Some antioxidants seem to have some evidence in their favor, for example apocynin and glutathione.

There's a lot of lab evidence favoring anti-inflammatories, although their clinical trial track record has been one of dismal failure for reasons I've ranted vehemently about elsewhere.

The theory obviously needs some oversimplification, and in the end it won't explain everything. It might however provide some useful clues toward effective therapeutics.

THE THEORY DU JOUR

1. Oxidative stress is a bad thing. In fact, a major feature of ALS.

2. Oxidation drives life. However, maloxidation creates molecular garbage, and some types of that garbage tend to collect into piles on their own, or are perhaps collected into piles by mechanisms currently poorly understood.

3. The body doesn't want these piles of garbage clogging up the cellular machinery, therefore mechanisms have evolved to recognize piles of garbage and to deal with them.

4. Once such method is to collect the garbage and dump it in a sequestered landfill: organalles exist for this purpose. Of course not all garbage is recognized as such and therefore escapes garbage collection.

5. Another such method is to break the garbage up into smaller pieces and either recycle them or piss them out. The metropolitan equivalent is recycling bins and flush toilets.

6. Inflammation in the broad sense is a life-preserving process: its functions are to promote oxidation of pathogens and anything else that got in the way; and then to dispose of the garbage. Most of the time this is uncomfortable, but better that than the discomfort of dying from infection. However some inflammatory processes are slow enough not to cause discomfort, leading us to (for instance) consume foods that lead to cardiovascular disease which is a scourge of the elders rather than of the youngers.

7. Heat shock protein is not one thing, there are many kinds differentiated by what sorts of molecular garbage they can recognize. Unlike the dumpster in my apartment complex which collects everything from plastic bags to leftover pizza and mattresses that have been pissed on too many times, the said dumpster being tipped over into trucks for transport to the same landfill, cellular evolution has been going on for billions of years and is much more sophisticated and specialized. A whole lot of sorting goes on.

8. So we've got these pathogenic processes going on in the normal body, and also in ALS. And we've got these cleanup processes going on in the normal body, and also in ALS. The difference is that in ALS, everything got out of balance.

9. There are many lines of evidence pointing to upstream causes (esp. relating to calcium imbalance resulting from glutamate imbalances). The "theory of ALS" I'm proposing here is not directly concerned with root cause (for example genetic SOD1 defect), but with how the body deals with the aftermath. Armchair philosophers may have the privilege of becoming obsessed with "root cause" but ALS is a disease mostly of oldsters already dealing with aftermath and in many cases (for example SOD1 genetic defect) having no control over root cause anyhow. .....Theories of root cause will eventually become important but right now the theories that matter most are those relating to managing ALS rather than "curing it". It is after all many diseases anyhow, no one pill is going to be "the cure". A specific example of this is prospective "cures" for the SOD1 genetic defect. One is already under development, an antisense SOD1 variant. It isn't likely to help anyone who doesn't have that genetic defect. ......Most of clinical medicine is not concerned with cause, it's concerned with dealing with the aftermath of the cause. The causes of medical problems are mostly war and its economic aftermath, lack of adequate sanitation practices, and some combination of too much bad food or not enough good food. Those are things in the realm of politics and macroeconomics, at the clinical level there is little control over such things, clinicians are dealing with the aftermath of society's mistakes rather than being able to prevent those mistakes in the first place.

10. So, in ALS we have oxidative stress, and despite that we have failure of autophagy. We need to fix the deficiencies in autophagy, and we also need to fix the oxidative stress. The trick is to fix both, which means fixing oxidative stress without impairing autophagy.

11. Not all antioxidants are created equal, they differ in kind, not just in "ORAC" rating. Not all autophagy boosters are created equal. To the extent that HSP's are involved in autophagy, not all HSP's are created equal. To the extent that anti-inflammatories may be involved in HSP/antioxidant/autophagy processes, they aren't created equal either.

12. ALS is often viewed as an accelerated aging process. This tends to be misleading because the people it tends to strike are people who are otherwise in good health, with a seeming preference for marathon athletes (!), it does occasionally hit younger people (for example Stephen Hawking who otherwise seems to be aging quite well!), and among ALS oldsters they seem almost always to die of complications of ALS and not from the kinds of stuff people that age should be dying from such as cancer and heart disease. It almost looks like the mostly unknown risk factors for ALS are in general present in the genome because they are otherwise protective against other degenerative diseases. We've even seen this in reference to Alzheimer's, which has a lot in common with ALS but it's evidently rare for a patient to have both conditions. It's entirely possible that in the big picture, the reason some people get ALS is because the underlying genetic war against the more common diseases just happened to dial the wrong number.

13. When it comes to ALS therapeutics, the state of the art is to take a shot in the dark, and to do it with a shotgun not a carbine.

14. I propose curcumin as the first such therapeutic that should be on the list. It is best known as an anti-inflammatory, and there's gobs of evidence in favor of anti-inflammatories in principle even when specific anti-inflammatories fail in crap clinical trials. Curcumin is an HSP inducer, which probably means it accelerates autophagy. Yes, it crosses the blood-brain barrier. It is not commonly thought of as an antioxidant although it is alleged to have antioxidant properties.

15. I propose as second line of defense, glutathione support. Not all antioxidants are created equal, but this one has anecdotal evidence in its favor in ALS. I regard JoelC's case as especially compelling. Like Aketri, he may not be posting here any more, but he gave us an extremely valuable gift in the quest for effective therapeutics. My personal experience is that when I run out of NAC and forget to replenish it, within a week my symptoms remind me to get with it, dude!

16. In this forum, there have been quite a few credible reports of therapeutic success in stopping the ALS neurodegenerative cascade and even reversing it at least temporarily. So it's not as though ALS is an "untreatable disease". ......I don't know what happens over at PLM, I got banned there. However I suspect based on what I've seen, that most patients who provide credible reports of therapeutic success are taking curcumin and are also doing antioxidant regimes which amount to "glutathione support".

17. In any theory of "what goes wrong in ALS", one pile of evidence resides in what people have done with some degree of success to treat it.

18. That pile of evidence (as I interpret it) indicates that antioxidant therapy that doesn't target the glutathione cycle effectively is probably ineffective; that anti-inflammatories that don't target autophagy are potentially useful; and that therapeutics which target autophagy show promise even if they don't happen to be regarded also as anti-inflammatories.

--Dave J.