In this post I try to provide an overview of ALS (Amyotrophic Lateral Sclerosis, aka Lou Gehrig's disease) theories. I just start with a few theories and hope to enlarge this post over time and with your help. I mark the places most in need for help by _?_. And additional references are of course always appreciated...

This thread is a spin off of http://www.als.net/forum/Default.aspx?g=posts&t=48200 and was inspired by other theories spread over different threads. I thought it would be helpful to have one place where they are summarized. The idea is not to discuss individual theories (I think the existing threads are a good place to do so) but just to give an overview and little, but important information on each theory. I don't make a difference between full sized theories and smaller parts that may fit into several theories as I don't feel able to clearly find the borderline between them.

I thought the following information could be important:
Theory type: ALS is a chronic illness and has most likely a cascade of events moving it forward. There may also be a cause that starts this cascade – like a hotplate igniting a house. The cause may just trigger the cascade or persist during the cascade.
Compatibility: The theory could fit well with other theories. Contradiction between theories is hard to prove since one theory (e. g. Genetics) may apply on some patients – but a contradicting theory may apply in other patients.
Manifestations (estimated percentage): The theory could apply in different ways; e. g. a viral infection could be caused by different viruses. The percentage gives an estimation on how many ALS patients may fall in each category.
Verification: How could the theory be tested? If it was tested: What were the results?
Treatments: What treatments could be deduced from this theory? If they were tested: What were the results? Treatment classes:
Unknown: I wasn't able to put it in one of the following classes
Idea: Just an idea about treatments that could possibly be effective. In no way proven.
No prove known: Theory or usage in other diseases suggest that this could be helpful. In no way proven.
In vitro successful: Trials in test tubes suggest that this could be helpful. In no way proven in human subjects.
In vivo successful: Trials in animal model suggest that this could be helpful. In no way proven in human subjects.
Phase 0 successful: Preliminary low dose tests on humans. Does not prove the safety or efficacy.
Phase 1 successful: First real testing in usually healthy human subjects to prove the safety. Does not prove the efficacy.
Anecdotal report: Somebody reports effects. This does not prove the safety or efficacy.
Phase 2 successful: Tests for safety and efficacy in patients.
Phase 3 successful: Definitive assessment.
Standard: Is used by physicians as a standard treatment for this purpose.

And here they are in alphabetical order:

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Theory name: Autoimmune was renamed to Immune System Dysregulation
see below

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Theory name: Axonal transport theory
Theory type: Unclear
In one sentence: Axonal transport mechanisms do not work correctly.
See also: -
Compatibility: -
Manifestations (estimated percentage):
_?_
Verification:
_?_
Treatments:
_?_
References:
[1] see Dave J's post below

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Theory name: Bacterial infection
Theory type: Cause and cascade
In one sentence: Bacteria or bacterial toxins attack the nervous system
See also: Fungal infection, Viral infection
Compatibility: Free radicals / oxidative damage, toxins
Manifestations (estimated percentage):
- BMAA: The toxic amino acid BMAA that is created by Cyanobacteria was found in ALS brain tissue. [3][4]
- Lyme disease, or lyme borreliosis (_?_)
- Spirochetes
_?_
Verification:
_?_
Treatments:
Lyme disease:
- Unknown: Tests (no one is 100% reliable): Antibody (ELISA, Westernblot), LTT, FACT [1]
- Standard: Therapies: Antibiotics (e.g. Ceftriaxone); some other antibiotics attack the mitochondrial function and may do harm if the Mitochondrial dysfunction theory applies. [1]
References:
[1] Gesund statt chronisch krank, Dr. med. Joachim Mutter, fit fürs Leben Verlag, 2009
[2] Interaction between MND and bacterial infection in mice:
- Abstract: http://www.jneurosci.org/cgi/content/abstract/24/6/1340
- Full version: http://www.jneurosci.org/cgi/reprint/24/6/1340.pdf
[3] http://informahealthcare.com/doi/abs/10.3109/17482960903268676
[4] see halfins post below
_?_

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Theory name: Calcium overload in nerve cells
Theory type: Cascade
In one sentence: Calcium overload in nerve cells causes apoptosis.
See also: -
Compatibility: Mitochondrial dysfunction, Proteinopathies - Autophagy dysfunction and neurodegeneration
Manifestations (estimated percentage):
_?_
Verification:
_?_
Treatments:
_?_
References:
[1] http://www.nature.com/ncb/journal/v5/n12/full/ncb1203-1041.html
[2] Link between calcium overload and proteinopathies: http://www.als.ca/_media/docs/NorthernNeuron2010-web.pdf , page 36
[3] Calcium, autophagy, protein degradation: http://www.ncbi.nlm.nih.gov/pubmed/20097418
[4] Calcium and Ryanodine receptor:
- http://www3.interscience.wiley.com/cgi-bin/fulltext/119266740/PDFSTART?CRETRY=1&SRETRY=0
[5] Thread on Caffeine, discussion on [3] and [4]: http://www.als.net/forum/Default.aspx?g=posts&t=48212&p=2
[6] Thread with many references to calcium: http://www.als.net/forum/Default.aspx?g=posts&t=48300

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Theory name: Cervical spine trauma
Theory type: Cause
In one sentence: A cervical spine trauma causes the generation of free radicals and starts the vicious circles as described in the Free radicals / oxidative damage theory.
See also:
_?_
Compatibility: Free radicals / oxidative damage, Mitochondrial dysfunction
Manifestations (estimated percentage):
_?_
Verification:
Patients anamnesis, documented cases without causality [1]
Causality _?_
Treatments:
- Anecdotal report: Protocol involving several steps. [1]
References:
[1] Das HWS-Trauma: Ursache, Diagnose und Therapie, Dr. med. Bodo Kuklinsky, Aurum im Kamphausen Verlag, 2006
[2] Trauma or other cervical spine disorder - Myodural bridge: http://www.als.net/forum/Default.aspx?g=posts&t=48203&p=2
[3] Head trauma and APOE genotype associated with ALS: http://www.ncbi.nlm.nih.gov/pubmed/20129626

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Theory name: Chronic regeneration failure
Theory type: Cascade
In one sentence: A chronic failure in the first stage of cellular regeneration however caused, this relates to other diseases as well as familial and sporadic ALS.
See also: -
Compatibility: Compatible with all theories mentioned in this overview. Also compatible with Dave J’s overview on the ALS degenerative cascade theory, (the failure of regeneration leads to degeneration), and his “other theories of neurodegeneration”.
Manifestations (estimated percentage):
First stage of cell specific repair failure for fALS and sALS - 100%.
Verification:
Mice could be subjected to a chronic physical muscular injury in the first place, to see if ALS results. A transgenic mouse could then be developed to replicate the chronic injury state without an actual injury.
Treatments:
- Idea: Must concentrate on the very start of regeneration. Everything downstream from this will require a separate treatment for both familial and sporadic conditions, and the cause will always be fighting the treatment.
- In vivo: Intravenous folate [3] [4]
References:
[1] http://www.als.net/forum/Default.aspx?g=posts&t=48200
[2] see David Hicks Post below
[3] Forum post on axonal regeneration and intravenous folate: http://www.als.net/forum/Default.aspx?g=posts&t=46397
[4] Article on axonal regeneration and intravenous folate:
- http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2860927/?tool=pubmed
[5] Spinal Axon Regeneration in Nogo-, MAG-, and OMgp-Deficient Mice:
- http://www.cell.com/neuron/abstract/S0896-6273%2810%2900367-3

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Theory name: Degenerative cascade theory
Theory type: Cascade
In one sentence: Increased extracellular glutamate → increased calcium influx in the neuron → triggers release of energy from mitochondria in the neuron → mitochondria get out of balance and produce excess free radicals → free radicals impair the mitochondria further → intracellular calcium raises and finally the neuron dies → the dying neuron increases extracellular glutamate → the cascade continues ...
See also: Calcium overload in nerve cells, Free radicals / oxidative damage, Glutamate toxicity
Compatibility: -
Manifestations (estimated percentage):
“Things like this probably happen” (~100%)
Verification:
_?_
Treatments:
- see section 'Propositions for combined treatments' below
References:
[1] see Dave J's post below
see references for the theories mentioned under See also:

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Theory name: Fungal infection
Theory type: Cause and cascade
In one sentence: Fungi or fungal toxins (e.g. ammonia) attack the nervous system
See also: Bacterial infection, Viral infection
Compatibility: Free radicals / oxidative damage, toxins
Manifestations (estimated percentage):
_?_
Verification:
_?_
Treatments:
_?_
References:
_?_

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Theory name: Food components or ingredients
Theory type: Cause
In one sentence: Food components or ingredients or sensitivity to these may cause or favor ALS.
See also: Toxins
Compatibility: Free radicals / oxidative damage
Manifestations (estimated percentage):
- Glutamate
- Aspartame
- Ricin [1]
- Naturally occuring toxins in fish
_?_
Verification:
_?_
Treatments:
- Change diet to avoid these components
_?_
References:
[1] see Mary Reids post below
_?_

---

Theory name: Free radicals / oxidative damage
Theory type: Cause and cascade
In one sentence: Vicious circles driven by free radicals (especially NO/ONOO-) promote apoptosis signaled by ONOO- (peroxynitrite)
See also: -
Compatibility: -
Manifestations (estimated percentage):
_?_
Verification:
_?_
Treatments:
- Anecdotal report: [1]
_?_
References:
[1] Explaining “unexplained illnesses”, Martin L. Pall, PhD, Informa Healthcare, 2007
[2] Thread with links to articels about zinc supplementation: http://www.als.net/forum/Default.aspx?g=posts&t=48314
_?_

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Theory name: Fungal infection
Theory type: Cause and cascade
In one sentence: Fungi or fungal toxins (e.g. ammonia) attack the nervous system.
See also: Bacterial infection, Viral infection
Compatibility: Free radicals / oxidative damage, toxins
Manifestations (estimated percentage):
_?_
Verification:
_?_
Treatments:
_?_
References:
_?_

---

Theory name: Genetics
Theory type: Cause
In one sentence: Genes control a misbehavior leading to ALS.
See also: -
Compatibility: -
Manifestations (estimated percentage):
- ANG; encoding angiogenin3
- FUS = TLS = ALS6; fused in sarcoma/translated in liposarcoma (_?_)
- OPTN; gene encoding optineurin (_?_) [5]
- SOD1; Superoxid dismutase 1 (~2%)
- TAR; TARDP encoding transactive response
- TDP-43; DNA-binding protein (_?_)
_?_
Verification:
_?_
Treatments:
- Enrolling SOD1 Positive FALS for Arimcomol Phase II/III trial [4]
- Trials running / planned: Pioglitazone [5]
References:
[1] Forum comment with links on TDP-43: http://www.als.net/forum/Default.aspx?g=posts&m=324274&#324274
[2] TDP-43 mouse model recreates an ALS-like phenotype: http://jaxmice.jax.org/strain/010700.html
[3] Misfolded SOD seeds amyloid fibrils: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0010627
[4] SOD Phase II/III trial enrollment, Arimcomol: http://www.als.net/forum/Default.aspx?g=posts&t=48234
[5] OPTN: http://www.als.net/forum/Default.aspx?g=posts&t=48173
[6] Connections between FUS, SOD1, TDP-43: http://www.als.ca/_media/docs/NorthernNeuron2010-web.pdf , page 31
[7] TDP-43 in fruit fly/drosophila: http://www.alscenter.org/news/rss_from_the_packard_center/10_06_02.html
[8] Thread with links on FUS=TLS=ALS6: http://www.als.net/forum/Default.aspx?g=posts&t=46947
[9] Forum response committee: FUS and SOD1: http://www.als.net/forum/Default.aspx?g=posts&t=48186&p=3
[10] Thread on SOD1 and microglia: http://www.als.net/forum/Default.aspx?g=posts&t=48316
[11] MicroRNA Malfunction in MND: http://www.als.net/forum/Default.aspx?g=posts&t=48318
[12] SOD-1, Caspase-1: http://www.als.net/forum/Default.aspx?g=posts&t=48322
[13] TDP-43: http://www.als.net/forum/Default.aspx?g=posts&t=48214
[14] Thread on TDP-43 and FUS: http://www.als.net/forum/Default.aspx?g=posts&t=48368

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Theory name: Glia/astrocyte hypothesis
Theory type: Unclear
In one sentence: A disease of the glia cells / astrocytes that support the neurons from outside causes damage to neurons.
See also: -
Compatibility: -
Manifestations (estimated percentage):
_?_
Verification:
_?_
Treatments:
- Idea: Biological growth factors
- Idea: Stem cell therapy
- In vivo: Bone marrow transplant for microglia (not ALS) [3]
References:
[1] see Dave J's post below
[2] Neurons and supporting cells in ALS (SOD-mice): http://www.als.net/forum/Default.aspx?g=posts&t=48228
[3] In vivo bone marrow transplant for microglia (not ALS): http://www.sciencedaily.com/releases/2010/05/100527122150.htm
[4] Thread on SOD1 and microglia: http://www.als.net/forum/Default.aspx?g=posts&t=48316
[5] Thread on astrocytes and adenosine: http://www.als.net/forum/Default.aspx?g=posts&t=48364

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Theory name: Glutamate toxicity
Theory type: Unclear
In one sentence: Glutamate toxicity leads to loss of motoneurons.
See also: -
Compatibility: -
Manifestations (estimated percentage):
_?_
Verification:
_?_
Treatments:
- Standard: Riluzole / Rilutec
- Phase II failed: Talampanel (an AMPA-Antagonist) [1] [2]
- Phase II in progress: Memantine, results not yet significant [3]
References:
[1] Talampanel Phase II results: http://www.tevapharm.com/pr/2010/pr_932.asp
[2] Forum comment on [1]: http://www.als.net/forum/Default.aspx?g=posts&t=48207
[3] Memantine, intermediate Phase II results: http://www.als.ca/_media/docs/NorthernNeuron2010-web.pdf , Page 16

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Theory name: Haemodynamic mechanism
Theory type: Unclear
In one sentence: ALS is caused by constrictions in veins draining the spinal cord and brain, which cause venous reflux, which downregulates tight junction proteins Occludin and ZO-1, which leads to breaks in the tight junctions between endothelial cells in the veins, which leads to leakage of toxic blood components into CNS tissue. [1]
See also: -
Compatibility: -
Manifestations (estimated percentage):
_?_
Verification:
_?_
Treatments:
_?_
References:
[1] http://www.als.net/forum/Default.aspx?g=posts&t=48172
[2] more pros and cons: http://www.als.net/forum/Default.aspx?g=posts&t=48172&p=2
[3] muscle loss linked to blood vessels' failure to dilate: http://www.als.net/forum/Default.aspx?g=posts&t=48216

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Theory name: Hypermetabolism theory
Theory type: Unclear
In one sentence: The metabolism is accelerated and muscle loss results from depletion of redox reserve of the muscle itself or of the neuromuscular junction.
See also: -
Compatibility: Neuromuscular junction theory
Manifestations (estimated percentage):
_?_
Verification:
_?_
Treatments:
- Idea: Modified ketogenic diet high in Omega-3
References:
[1] see Dave J's post below

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Theory name: Immune System Dysregulation
Theory type: Unclear
In one sentence: The immune system attacks nerve or glia cells.
See also: -
Compatibility: -
Manifestations (estimated percentage):
_?_
Verification:
_?_
Treatments:
- In vivo: Immune system modulation [1]
References:
[1] ALS-TDI 0086 paper: Anti-CD40L treatment in SOD1 mouse model:
- http://www.nature.com/ng/journal/v42/n5/full/ng.557.html#/abstract
[2] Thread on extracellular ATP as a cytotoxic factor and pro-inflammatory mediator:
- http://www.als.net/forum/Default.aspx?g=posts&t=48271
[3] Thread on Neuraltus:
- http://www.als.net/forum/Default.aspx?g=posts&t=48293
[4] Thread on Luteolin and Plants' Flavonoids
- http://www.als.net/forum/Default.aspx?g=posts&t=46322

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Theory name: Iron Homeostasis Dysregulation
Theory type: Unclear
In one sentence: Excess iron affects nervous system.
See also: -
Compatibility: -
Manifestations (estimated percentage):
_?_
Verification:
- In vivo: Positive effects with iron chelator on SOD mice [1]
_?_
Treatments:
- In vivo: Positive effects with iron chelator on SOD mice [1]
References:
[1] Iron chelator on SOD mice: http://www.als.ca/_media/docs/NorthernNeuron2010-web.pdf , Page 21
[2] Forum thread on iron: http://www.als.net/forum/Default.aspx?g=posts&t=46850

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Theory name: Lipotoxicity
In one sentence: The imbalanced energy homeostasis that elicits obesity and further leads to insulin resistance
and type 2 diabetes, fatty liver and a range of other disorders, generally known as the metabolic syndrome, may in leaner individuals instead manifest itself as a form of lipotoxicity in the CNS, which causes ALS.
See also: Proteinopathies - Autophagy dysfunction, Neuromuscular junction theory (Lrp4-References), Liver disease
Compatibility: Misfolded proteins, inclusions, ER-stress, Mitochondrial dysfunction
Manifestations (estimated percentage):
- ? -
Verification:
Null mutant mice for the nuclear receptor liver X receptor beta (LXRβ, a ligand-activated transcription factor which induces genes controlling cholesterol homeostasis and lipogenesis) faithfully reproduces the ALS phenotype. Feeding β-Sitosterol (a plant sterol with cholesterol lowering properties) to LXRβ-null mice further aggravates the MN disease phenotype.
Treatments:
- Idea: Manipulation of diet and/or of key enzymes, such as AMP-activated protein kinase (AMPK, e.g. with AICAR) and fatty acid synthase (FAS), as well as intermediate metabolites, such as malonyl-CoA and long-chain fatty acids-CoA (LCFAs-CoA).
- In vivo: Lithium has antiinflammatory effects on fatty acids. [4]
- Anecdotal reports / Phase 2, 3 study failed. _?_
References:
[1] http://pathology.unige.ch/patho/biomol/documents/Reviewhypothalamiclipotoxicity_000.pdf
[2] http://diss.kib.ki.se/2009/978-91-7409-307-0/thesis.pdf
[3] http://www.fasebj.org/cgi/content/meeting_abstract/23/1_MeetingAbstracts/LB396
[4] Forum post with article links on lithium in rats: http://www.als.net/forum/Default.aspx?g=posts&t=48223
[5] High LDL/HDL increased survival in patients by more than 12 months:
- http://www.neurology.org/cgi/content/abstract/70/13/1004
[6] Thread with reference on cholesterol and neuroinflammation:
- http://www.als.net/forum/Default.aspx?g=posts&t=48243

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Theory name: Liver disease
Theory type: Unclear
In one sentence: An incorrect liver function leads to sterol metabolism disorder which in turn and over time may leed to ALS.
See also: -
Compatibility: -
Manifestations (estimated percentage):
_?_
Verification:
_?_
Treatments:
- Idea: Ursodiol? see section Treatments not linked to a specific theory below
_?_
References:
[1] http://als.net/forum/Default.aspx?g=posts&m=323801
[2] Minireview LXR beta, http://mend.endojournals.org/cgi/reprint/23/2/129

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Theory name: Mechanical disorder, injury or trauma
Theory type: Cause
In one sentence: Mechanical injury of muscles, nerves, cervical spine or head may cause or favor ALS.
See also:
_?_
Compatibility: Free radicals / oxidative damage, Mitochondrial dysfunction
Manifestations (estimated percentage):
- Cervical spine trauma causes the generation of free radicals and starts the vicious circles as described in the Free radicals / oxidative damage theory.[1]
- Neuromuscular mechanical injury
- Head trauma [3]
- Myodural bridge [2]
_?_
Verification:
Patients anamnesis, documented cases without causality [1]
Causality _?_
Treatments:
- Anecdotal report: Protocol involving several steps. [1]
References:
[1] Das HWS-Trauma: Ursache, Diagnose und Therapie, Dr. med. Bodo Kuklinsky, Aurum im Kamphausen Verlag, 2006
[2] Trauma or other cervical spine disorder - Myodural bridge: http://www.als.net/forum/Default.aspx?g=posts&t=48203&p=2
[3] Head trauma and APOE genotype associated with ALS: http://www.ncbi.nlm.nih.gov/pubmed/20129626

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Theory name: Mitochondrial dysfunction
Theory type: Cascade
In one sentence: The mitochondria are not able to provide enough energy so that the cell can't do it's job correctly – especially so that it can't pump out the calcium out of the nerve cells and that this leads to apoptosis.
See also: -
Compatibility: Calcium overload in nerve cells, Free radicals / oxidative damage
Manifestations (estimated percentage):
_?_
Verification:
_?_
Treatments:
- Unknown: see [1]
References:
[1] http://www.lef.org/magazine/mag2010/feb2010_Reverse-Mitochondrial-Damage_01.htm
[2] Thread with reference on mitochondria and ALS: http://www.als.net/forum/Default.aspx?g=posts&t=48288
[3] Thread on ATP, Actovegin, AICAR: http://www.als.net/forum/Default.aspx?g=posts&t=48321

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Theory name: Neuromuscular junction theory
Theory type: Unclear
In one sentence: The junction of the lower motor neuron and the muscle disconnect due to hitherto unknown reasons.
See also: -
Compatibility: -
Manifestations (estimated percentage):
_?_
Verification:
_?_
Treatments:
_?_
References:
[1] see Dave J's post below
[2] Signaling in Drosophila larva: http://www.als.net/forum/Default.aspx?g=posts&t=48251
[3] LDL-Cholesterol, Lrp4 and Neuromuscular junctions: http://www.spacedoc.net/ldl_cholesterol_neuromuscular
[4] Lrp4, used in [3]: http://www.newsrx.com/article.php?articleID=1311804
[5] Full article of [4]: http://www.cell.com/content/article/fulltext?uid=PIIS0092867408012506
[6] Muscle gene regulations precede the onset of paralysis in mSOD1 mice and lots of background:
- http://physiolgenomics.physiology.org/cgi/reprint/32/2/207

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Theory name: Nuclear or electrical radiation or electric or magnetic fields
Theory type: Cause
In one sentence: Radiation or fields or sensitivity to these may cause or favor ALS.
See also: -
Compatibility: Free radicals / oxidative damage
Manifestations (estimated percentage):
_?_
Verification:
_?_
Treatments:
- Change or avoid sources
_?_
References:
_?_

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Theory name: Pervasive disturbed tubulin interactions
Theory type: Unclear
In one sentence: Mutant SOD1, tubulin and neurofilaments colocate in protein aggregates. Tyrosine nitration primarily of tubulin and possibly oxidation of wild type SOD contribute to this end.
See also: Free radicals / oxidative damage, Genetics, Proteinopathies - Autophagy dysfunction and neurodegeneration
Compatibility: Immune System Dysregulation, Axonal Transport, Chronic regeneration failure, Degenerative cascade theory, Lipotoxicities, Glutamate toxicity, Neuromuscular junction theory, Toxins
Manifestations (estimated percentage):
_?_
Verification:
_?_
Treatments:
- Idea: Catalase, Peroxidase [1]
References:
[1] see royalfig's post below
[2] Wild type SOD similar to mutated SOD: http://www3.interscience.wiley.com/cgi-bin/fulltext/118484006/PDFSTART?CRETRY=1&SRETRY=0
[3] Early axonal transport failure on mutated SOD: http://www.ncbi.nlm.nih.gov/pubmed/10195180

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Theory name: Proteinopathies - Autophagy dysfunction and neurodegeneration
Theory type: Unclear
In one sentence: Many late-onset neurodegenerative diseases, including ALS, Alzheimer's disease Parkinson’s disease and Huntington’s disease, are associated with the formation of intracellular aggregates by (toxic) proteins.
See also: Genetics
Compatibility: -
Manifestations (estimated percentage):
- A majority, if not all currently available ALS-model systems
- Prions may fall into this category - or be regarded as infectious particles
Verification:
Lack of autophagy is associated with neurodegeneration, even in the absence of harmful gene products
found in neurodegenerative disorders such as ALS, AD, HD & PD
Treatments:
- Idea: Decrease the expression of the aggregate-prone protein(s) and/or enhance protein aggregate degradation.
References:
[1] http://linkinghub.elsevier.com/retrieve/pii/S001457931000325X
[2] Misfolded SOD seeds amyloid fibrils: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0010627
[3] Company addressing aggregated misfolded protein diseases : http://www.amorfix.com/
[4] Press release on ALS-vaccine in development by [3]: http://www.tradingmarkets.com/news/stock-alert/arfxf_amorfix-life-sciences-and-prevent-sign-licensing-agreement-966098.html
[5] Forum thread on [3], [4]: http://www.als.net/forum/Default.aspx?g=posts&t=48259
[6] Background information on this type of vaccination: http://www.als.ca/_media/docs/NorthernNeuron2010-web.pdf , Page 22
[7] FALS type misfolded SOD does not appear in sporadic ALS: http://www.als.ca/_media/docs/NorthernNeuron2010-web.pdf , page 35
[8] Angiogenin as a cause of MND: http://www.als.net/forum/Default.aspx?g=posts&t=48277
[9] Thread on autophagy promotion by HSPB's: http://www.als.net/forum/Default.aspx?g=posts&t=48309
[10] Thread on lysosome disfunction: http://www.als.net/forum/Default.aspx?g=posts&t=48353
[12] Thread on TDP-43 and FUS: http://www.als.net/forum/Default.aspx?g=posts&t=48368

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Theory name: Sequel of a medical treatment
Theory type: Cause
In one sentence: A previous medical treatment caused unindentendly changements in the patients body leading to or favoring ALS.
See also: -
Compatibility: Toxins, Mechanical disorder, injury or trauma
Manifestations (estimated percentage):
- sequel of cancer chemotherapy
- sequel of surgical anesthesia
- sequel of the use of anticholinergic drugs
- sequel of the use of statins
- sequel of immunization
- - Polio
- - Herpes
- - TBE
_?_
Verification:
_?_
Treatments:
_?_
References:
[1] Statins: see Dave J.s post below

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Theory name: Sequel of extreme sports
Theory type: Cause
In one sentence: Extreme sports or physical stress causes or favors ALS possibly by free radicals or mechanical stress.
See also: -
Compatibility: Free radicals / oxidative damage, Mechanical disorder, injury or trauma
Manifestations (estimated percentage):
_?_
Verification:
_?_
Treatments:
_?_
References:
_?_

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Theory name: Sequel of severe electric shock
Theory type: Cause
In one sentence: Severe electric shock causes or favors ALS.
See also: -
Compatibility: -
Manifestations (estimated percentage):
_?_
Verification:
_?_
Treatments:
_?_
References:
_?_

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Theory name: Toxins
Theory type: Cause
In one sentence: Toxins do direct damage to nerve, glia and/or muscle cells or do damage to other organs that leads in turn to ALS.
See also: Bacterial, fungal and viral infections
Compatibility: Free radicals / oxidative damage
Manifestations (estimated percentage):
- Metals:
- - Aluminum (_?_)
- - Lead (_?_)
- - Mercury (_?_)
- Agricultural
- - Herbicides
- - Pesticids
- Biochemical weapons or counterweapons
_?_
Verification:
_?_
Treatments:
- Anecdotal reports: Remove toxin sources (Beware from side effects!)
- Anecdotal reports: Remove toxins from body (Beware from side effects!)
_?_
References:
[1] Thread on formaldehyde: http://www.als.net/forum/Default.aspx?g=posts&t=46172

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Theory name: Viral infection
Theory type: Cause
In one sentence: Viruses attack the nervous system.
See also: Bacterial infection, Fungal infection
Compatibility: -
Manifestations (estimated percentage):
- Herpes zoster (_?_)
- Human herpes virus 6 / (HHV-6 (_?_)
- Poliovirus
- Retroviruses
_?_
Verification:
_?_
Treatments:
_?_
References:
[1] Poliovirus, with references: http://www.als.net/forum/Default.aspx?g=posts&t=46947 , see Mary Reids Post
[2] Genes activated by virus: http://www.als.net/forum/Default.aspx?g=posts&t=48311
[3] Poliovirus, retroviruses: http://www.als.net/forum/Default.aspx?g=posts&t=48267

---

Theories in need for clarification / more background:
- Association with metabolic syndome? http://www.als.net/forum/Default.aspx?g=posts&t=48203&p=2 , Dave J. s post on 6/3/2010

---

Treatments not linked to a specific theory:
- Acetyl-L-Carnitin:
- - No prove known: http://www.als.net/forum/Default.aspx?g=posts&t=48299
- - Summary of several studys (commercial context): http://intelegen.com/nutrients/brain_regeneration_key_nutrients.htm
- Chondroitin sulfate: http://www.als.net/forum/Default.aspx?g=posts&t=48308
- Ginger for muscle pain: Anecdotal report: http://www.als.net/forum/Default.aspx?g=posts&t=48217
- KNS-760704 from Knopp Neurosciences
- - Thread with links, including positive Phase II results: http://www.als.net/forum/Default.aspx?g=posts&t=48027
- Methylcobalamin (one form of vitamine B12):
- - Inconsistent effectiveness: http://www.als.net/forum/Default.aspx?g=posts&t=48250
- Neurorprotecting agents:
- - Thread on Tocotrienol with link: http://www.als.net/forum/Default.aspx?g=posts&t=48367
- Neuroregeneration agents:
- - Thread: http://www.als.net/forum/Default.aspx?g=posts&t=48305
- - Thread on Drug grows brain cells: http://www.als.net/forum/Default.aspx?g=posts&t=48336
- - Thread on resveratrol and sirtuins promoting plasticity and memory: http://www.als.net/forum/Default.aspx?g=posts&t=48347
- Peony root and paeoniflorin: Thread with more links: http://www.als.net/forum/Default.aspx?g=posts&t=48193
- Physical exercise:
- - Beneficial for mice: http://www.expressnews.ualberta.ca/NewsArticles/2010/06/ExercisemayslowprogressionofALS.aspx
- Stem cells
- - Forum response committee on stem cells: http://als.net/forum/Default.aspx?g=posts&m=322931#322931
- - Stem cell for spinal cord injury, including extensive basic info: http://www.cellmedicine.com/spinal.asp
- - How stem cells navigate in mouse CNS: http://today.uci.edu/news/2010/06/nr_lane_100601.php
- - - Forum thread on this article: http://www.als.net/forum/Default.aspx?g=posts&t=48241
- - Thread on stem cell consumer guide: http://www.als.net/forum/Default.aspx?g=posts&t=48320
- - Neuralstem Phase I progresses:
- - - http://www.prnewswire.com/news-releases/neuralstem-updates-clinical-trial-progress-94735894.html
- - - 06/10/2010: http://www.als.net/forum/Default.aspx?g=posts&t=48286
- - - Update on Neuralstem Phase I: http://www.als.net/forum/Default.aspx?g=posts&t=48329
- - California stem cell: http://www.californiastemcell.com/
- - Adverse effects: http://www.als.net/forum/Default.aspx?g=posts&t=46693&p=2 , posts from 6/17/2010 and later
- Ursodiol: Possible effects: Anti-inflammatory, protects nerve cells etc.
- - Forum response committee on Ursodiol: http://www.als.net/forum/Default.aspx?g=posts&t=47542&p=2
- - Phase I successful: http://www.biomedsearch.com/nih/Safety-Tolerability-Cerebrospinal-Fluid-Penetration/19935406.html
- - Anecdotal report, positive: http://www.als.net/forum/Default.aspx?g=posts&t=47542 (Michele's post, Big Mike's post)
- - Anecdotal report, doubts: http://www.als.net/forum/Default.aspx?g=posts&t=47542&p=5 (manhattaner's post)
- - PATIENT DRIVEN STUDY: http://alsurso.atspace.com/index.html
- - Document with my full analysis of PLM-information on 07/01/2010: "Treatments-containing-Ursodiol-UDCA-2010-07-01.pdf"
- - - http://www.4shared.com/dir/aaQscxjW/Shared.html

---

Propositions for combined treatments:
[1] protect motor neurons, suppress damaging inflammation, protect mitochondria, suppress oxidative stress, etc. would likely have a good chance
[2] glutamate antagonists, antioxidants, a centrally acting anti-inflammatory agent, microglial cell modulators (including tumor necrosis factor alpha [TNF-alpha] inhibitors), an antiapoptotic agent, 1 or more neurotrophic growth factors, and a mitochondrial function-enhancing agent
[3] Anti-autoimmune, Anti-inflammatories, NMDA calcium channel blockers, AMPA calcium channel blockers, Voltage-gated calcium channel modulators, Mitochondrial redox support (including acetylcholine support), Mitochondrial reactive oxygen species & free radical protection, Protection against protein misfolding, Normalization of calcium transport, Co-factors, Neuron repair accelerators
[4] Anecdotal report
References:
[1] http://www.als.net/forum/Default.aspx?g=posts&t=48186&p=2
[2] First part of abstract: http://www.ncbi.nlm.nih.gov/pubmed/20439484
[3] see Dave J's post below
[4] http://www.als.net/forum/Default.aspx?g=posts&m=324431&#324431

APPROACHES TO TREATING A.L.S.



This essay pertains to treating the disease itself. Treatments which deal with symptoms, life support measures, etc. are not discussed.


“ALS” is not one disease, it is a collection of diseases most of which have no other specific name. A therapy which is beneficial for one patient may be of no value to another. Some therapies have substantial medical risk which must be balanced against the amount of benefit that might be achieved. And, some therapies are very expensive, the cost of which must be balanced against the amount of benefit that might be achieved. There is presently no therapy for ALS which is widely accepted among the scientific community as having substantial benefit, with the arguable exception of physical therapy.


When reading reports of apparent benefit, you need to be aware that ALS research has turned up evidence that “placebo effect” may in some patients result in stabilization or even improvement lasting as long as 3 months. It is also possible that some therapeutics are effective in treating one “link in the chain of neurodegeneration”, but within weeks to several months, events in the rest of the chain break that link. In the case of either placebo effect or “weak link treatment”, when it finally fails there is often a quick decline to the level of impairment that would have been present had there been no temporary benefit.


When reading reports of apparent benefit in “mouse trials”, you need to be aware that a lot of mouse trials have been poorly done and that the supposed success cannot be replicated. ALSTDI has become an outspoken critic of the quality of much mouse trial data and has reformed its own mouse trial protocols so that the reported results have a reasonable expectation of being repeatable by other experimenters adhering to the same high standards.



Five approaches to ALS therapy

1. On-label drugs. For now, there is only one-- Riluzole. It may not be of much value but at least there’s lots of information about it.


2. Doing what other patients have reported success in doing. Unfortunately most such reports of success are of sufficiently poor quality that it is difficult to determine what really happened. Some such reports in the general category of “commercial testimonials” are suspected of being fictional. One way to filter such reports is to do a little research to see if what’s being reported makes any kind of scientific sense. In medicine, sometimes things “work” without anyone knowing why, but a report that makes scientific sense is generally regarded as more credible than one which doesn’t.


3. Creating your own custom therapeutic regime based on a theory (or theories) of what goes wrong in ALS; then identifying drugs, supplements, herbs, or other specific therapeutics which you hope will correct the problem. Taking this approach requires some difficult research. There are many such theories to choose from and it is difficult to know what might apply to your particular case. Once you’ve chosen a theory (or theories) of what goes wrong, identifying what you can do about it can also take a lot of research, and you may come up empty-handed.


4. Experimental commercial therapies performed in clinics, for example “stem cell therapy”. Such commercial clinic therapies are usually expensive, their scientific basis is usually flimsy, and the reports of success are usually not documented well enough to distinguish from exaggeration or fiction.


5. Enrollment in a clinical trial. This should not usually be regarded as an “approach to therapy” since most clinical trials are trialing a substance of dubious therapeutic value (it’s rare that even the trial sponsors express much enthusiasm over the prospects); and most often about half the patients receive a placebo. Many clinical trial protocols require that the patient not engage in any other experimental therapy during the trial. Enrolling in a clinical trial should generally be regarded as contributing to scientific knowledge, not as getting “free treatment”.


Theories of cause


Identifying cause and effect in ALS has proven to be exceptionally difficult.


1. ALS is many diseases, not one.


2. Demographic research has produced some interesting data but nothing that points to any specific cause being especially important.


3. About 3% of ALS patients carry an inherited genetic defect which results in defective SOD-1 (an important antioxidant produced in the body). Despite massive amounts of research done in both humans and in the laboratory, there is still no consensus how defective SOD-1 causes ALS.


4. Many biochemical abnormalities have been found in ALS patients. However it is not always obvious whether a particular abnormality is a cause of the disease, a result of the disease, or both (i.e. part of a self-sustaining neurodegenerative process).


5. Some theories of cause presume years, even decades, of neurodegeneration taking place before symptoms develop which lead a patient to the doctor’s office. Other theories of cause presume an event which initiates a neurodegenerative process. Until a patient shows up in the doctor’s office complaining of ALS symptoms, there is almost never any earlier neurological or biochemical data available which might permit a determination what was going on in the patient’s body prior to the emergence of symptoms. That lack of presymptomatic data has greatly impeded understanding of both cause, and of the degenerative process itself. Some data has been collected from “SOD-1 defect” laboratory mice since researchers know these animals will develop ALS; however it is unknown what this data means in relation to the vast majority of human ALS patients who do not have that same genetic defect.


Theories of cause include: exposure to heavy metal toxins esp. lead and mercury, exposure to agricultural herbicides and pesticides, exposure to biochemical weapons and counterweapons (in war zones), nuclear radiation, infectious disease (esp. spirochetes, prions, and retroviruses), immunizations (esp. polio and herpes), exposure to cyanobacteria toxins, exposure to naturally occurring toxins in fish, sequel to severe electric shock, sequel to neuromuscular mechanical injury, sensitivity to dietary aspartame and/or glutamate, sequel to extreme exercise/sports (esp. marathons), sequel to neurological damage from cancer chemotherapy, sequel to neurological damage resulting from surgical anesthesia, use of anticholinergic drugs, use of statin drugs.


Treatment according to a theory of cause requires choosing a plausible cause in a particular patient, and then if possible treating that cause. In many cases treatment according to a theory of cause is not possible because the cause itself is no longer present, what remains is the neurological damage which left the nervous system vulnerable to degeneration.


Although sensitivity to dietary aspartame and/or glutamate is probably not adequate by itself to provoke ALS, it could theoretically be an element in the development of ALS. There is no risk or cost to eliminating aspartame and highly concentrated glutamates from the diet. For this reason quite a few “self-treaters” practice such a dietary restriction.


Low cholesterol is a risk factor in neurological disease, and the purpose of statin drugs is to lower cholesterol. Statins also deplete CoQ-10 which is necessary for neuromuscular health. The dangers of statin use in an ALS patient can probably be reduced by supplementing with CoQ-10, by using statins known to have a better safety profile esp. for muscle damage, and not to strive for cholesterol levels below about 200. After all, you’re not a typical patient, you’ve got ALS. One could also eliminate entirely the statins and either not treat cholesterol, or treat it through methods which pose less risk to an ALS patient. …… Once ALS has already been diagnosed, neurodegeneration will probably continue even if you re-manage or eliminate statins, but at least you’ll have reduced the risk that the statins are making matters worse.


Quite a few “self-treaters” have known or suspected exposure to high levels of toxic heavy metal toxins, and choose to undergo chelation therapy. Anyone choosing to do so needs to be aware of the following:

1. there are a lot of different chelation therapies, and they are not all created equal;

2. chelation runs the risk that immobilized toxins not presently in the nervous system may be remobilized
and enter the nervous system causing further neurological damage;

3. chelation is a medical specialty where if you’re doing it at all, it should be at the hands of someone who
really is an expert in it; and

4. even if chelation is successful, neurodegeneration will probably continue although possibly at a slower
rate.



Some “self-treaters” who have a lot of amalgam fillings in their teeth choose to have them removed. As with chelation, the risk is that in the process mercury which is presently immobilized in the fillings will become remobilized through breathing of vapors and ingestion of fragments, enter the nervous system, and cause further damage. If amalgam fillings are removed, it should be done by a dentist who specializes in this procedure and takes precautions against mercury going in any direction besides out.


It is widely believed by researchers that the primary “cause” of ALS is a mix of genetic factors which predispose a person to development of ALS, in combination with environmental factors which cause that latent tendency to become manifest. This explains why many persons can be exposed to a particular environmental risk factor (for instance statin drugs, which are known to deplete cholesterol and Co-Q10) yet only a few persons develop ALS as a result.



Theories of degenerative process


Given the problem of understanding a cause and treating that, many approaches to therapy are not concerned with the question of why this patient developed ALS, they are concerned with treating the neurodegenerative process itself regardless of cause.


Back in the 1990’s, research homed in on the role of glutamate imbalance in causing mitochondrial damage. This led to a theory often summarized as “the glutamate-induced degenerative cascade”. Since that time the basic theory of neuron degenerative cascade has expanded beyond focus on glutamate itself. There is no single “overall theory” since many of the elements in any version of an “overall theory” are open to dispute as to their relative importance. Even the word “overall” is misleading: who knows what’s missing? …..What follows here is an example of an “ALS degenerative cascade theory”. Although there is a lot of disagreement among researchers as to the relative importance of the various elements in this theory, there is a semblance of agreement that “things like this probably happen”. The importance of a theory of this type is that there are substances known which can be used to target various elements in this chain of events. The majority of drugs being clinically trialed for ALS have a scientific rationale based on some element of a “cascade”. For reasons peculiar to commercial drug development historical custom, clinical trials usually involve only one substance intended to target only one element of the “cascade”, resulting in the near-impossibility of demonstrating statistically significant patient benefit. If you’re creating your own therapeutic regime, you don’t have that limitation and can treat many of the elements of the cascade.


An ALS degenerative cascade theory


1. Events outside the motor neuron, for instance inflammation, increase glutamate concentration at the exterior of the neuron.


2. Glutamate opens the neuron’s voltage-gated calcium channels, allowing calcium ions (Ca++) to flow into the neuron.


3. The influx of Ca++ triggers the release of energy in the mitochondria of the neuron.


4. These things normally happen anyhow, but with neurodegeneration they happen at an increased rate.


5. The mitochondria’s ability to maintain energy-producing oxidation-reduction (“redox”) chemical reactions in balance is compromised, leading to free radical damage.


6. Free radical damage reduces the mitochondria’s ability to maintain redox in balance, such that even normal glutamate levels are sufficient to sustain the degenerative cascade.


7. The neuron’s ability to remove calcium from the neuron is also compromised, leading to further degradation of the neuron’s ability to maintain normal energy and repair processes.


8. The dying neuron releases biochemical signals which provoke inflammation, further sustaining the degenerative cascade.



Substances of possible usefulness in treatment according to the foregoing cascade theory


This list is not comprehensive. Emphasis is on substances which are already available and which are generally regarded as relatively safe or which the risks of which are well enough understood to be managed by a physician. This information is provided for the convenience of patients and doctors who wish to do their own research. No representation is made that anything listed here will be useful as therapy for any particular ALS patient.


Anti-autoimmune anti-inflammatories: Prednisone, Vitamin D3


Anti-inflammatories: NSAIDS, curcumin, Omega-3’s


NMDA calcium channel blockers: Memantine, magnesium, ethyl alcohol, dextromethophan


AMPA calcium channel blockers: Memantine?


Voltage-gated calcium channel modulators: GABA, taurine, ashwagandha, betaine (TMG), ethyl alcohol


Mitochondrial redox support (including acetylcholine support): N-acetyl cysteine, alpha lipoic acid, ubiquinol/ubiquinone, acetyl-L-carnitine, huperzine-A, citicoline, phosphadityl choline, R-ribose, creatine


Mitochondrial reactive oxygen species & free radical protection: N-acetyl cysteine, alpha lipoic acid, ubiquinol/ubiquinone, vitamin C, natural tocopherols (vitamin E) and tocotreinols, selenium, betaine (TMG), Picrorrhiza extract


Protection against protein misfolding Curcumin, peony root extract, resveratrol, L-carnosine


Normalization of calcium transport : Vitamin D3, vitamin K2, aequorin


Co-factors: B-vitamins (esp. B6,12), zinc, potassium


Neuron repair accelerators: Physical therapy & neuromuscular massage, carefully controlled exercise, getting a good night’s sleep, acetyl-L-carnitine arginate


Dietary support: Eliminate aspartame from diet; avoid foods containing high concentrations of added glutamate-based flavor enhancers



Other theories of neurodegeneration


Neuromuscular junction theory There is a lot of evidence to suggest that ALS begins with something gone wrong at the junction of the lower motor neuron and the muscle, causing the two things to disconnect. However this theory so far offers no satisfactory explanation of upper motor neuron disease which of course is a part of ALS and is the predominant feature in many patients. It is not clear what therapeutic options might be available to treat ALS according to the neuromuscular junction theory.


Axonal transport theory There is some evidence that failure of axonal transport mechanisms is a feature of neurodegeneration in ALS. It is not clear whether this is part of what initiates neurodegeneration or whether it is a result of neurodegeneration, or both. It is not clear what therapeutic options might be available to treat ALS according to the axonal transport theory.


The glia/astrocyte hypothesis Glial cells support neuron structure from the outside. There is some evidence that in ALS a disease process of glial cells causes damage to neurons. Therapeutic options include biological growth factors and stem cell therapy. It should be emphasized that stem cell therapy, although available if you’re wealthy enough, is strictly experimental, has serious risks, and has yet to produce convincing evidence of usefulness in treating ALS or any other neurodegenerative disorder.


Hypermetabolism theory Among patients who exhibit rapid muscle atrophy, there is some evidence that metabolism is accelerated and that muscle loss results from depletion of redox reserve of the muscle itself or of the neuromuscular junction. The primary therapy option presently being experimented with is a modified ketogenic diet high in Omega-3’s. It is not clear what other therapy options might be available.


* * * * * * * * * * * * * * *

--Dave J.

Thank you, Dave J. A really impressive overview! I added the Degenerative cascade theory - but there is still lots of information that I will take out of your post and integrate it as soon as I have some more time to spend. Just taking one step at a time...

Thanks, Nemesis - I integrated your post.

Dave, I added the "Other theories"-section of the sunday post and the link of the tuesday post. I added the new informaton "Theory type" - but there remains still some work to do from your sunday post..

reposted from the marijuana thread:

[quote=Lolo]Am J Hosp Palliat Care. 2010 May 3. [Epub ahead of print]
Cannabis and Amyotrophic Lateral Sclerosis: Hypothetical and Practical Applications, and a Call for Clinical Trials.
Carter GT, Abood ME, Aggarwal SK, Weiss MD.

University of Washington School of Medicine.
Abstract
Significant advances have increased our understanding of the molecular mechanisms of amyotrophic lateral sclerosis (ALS), yet this has not translated into any greatly effective therapies. It appears that a number of abnormal physiological processes occur simultaneously in this devastating disease. Ideally, a multidrug regimen, including glutamate antagonists, antioxidants, a centrally acting anti-inflammatory agent, microglial cell modulators (including tumor necrosis factor alpha [TNF-alpha] inhibitors), an antiapoptotic agent, 1 or more neurotrophic growth factors, and a mitochondrial function-enhancing agent would be required to comprehensively address the known pathophysiology of ALS.

PMID: 20439484 [PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/20439484
[quote]

*****************************************************************************
*****************************************************************************

Honest, folks, I didn't ghostwrite it!

Out of respect for that abstract, I will now sign my own name to it:

/s/ David E. Johnson
El Paso, TX USA
22 May 2010

There's no doubt in my mind that a multidrug regimen, for example including; glutamate antagonists, antioxidants, anti-inflammatory agents, antiapoptotic agents, neurotrophic growth factors, and a mitochondrial function-enhancing agent will be required to comprehensively address the known pathophysiology of ALS.

However, two central questions still remains to be answered. The first one is which specific combination of agents is approapriate for this coctail. The second question is why ALSTDI still after all these years, persists to look for single-drug magic-bullet treatment?

---

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.

Follow the tubulin. An interaction with tubulin can be found with every type of molecule mutated in ALS.

Donna C. King

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Here are some good pictures of tubulin.

http://www.connexin.net/microscopy-fluorescence-confocal-LSM-gallery.html

Donna C. King, could you give a summary about tubulin and its interactions?

Aketri,

This is my view on your “Chronic Regeneration” entry.

Theory name: Chronic regeneration failure.
In one sentence: A chronic failure in the first stage of cellular regeneration however caused, this relates to other diseases as well as familial and sporadic ALS.
See also: -?-
Compatibility: Compatible with all theories mentioned in this overview. Also compatible with Dave J’s overview on the ALS degenerative cascade theory, (the failure of regeneration leads to degeneration), and his “other theories of neurodegeneration”.
Manifestations: First stage of cell specific repair failure for fALS and sALS - 100%.
Verification: Mice could be subjected to a chronic physical muscular injury in the first place, to see if ALS results. A transgenic mouse could then be developed to replicate the chronic injury state without an actual injury.
Treatments: Must concentrate on the very start of regeneration. Everything downstream from this will require a separate treatment for both familial and sporadic conditions, and the cause will always be fighting the treatment.
References: [1] http://www.als.net/forum/Default.aspx?g=posts&t=48200

Here are some general comments on the above.

Only the real cause of ALS will be able to be connected to all of the above theories. To efficiently explain how each is connected will take a heap of work. What I hope is that ALS TDI publishes a wish list of questions that if answered would give them the confidence to test the theory that the answers were based on.
ALS TDI’s latest anti-CD40L treatment is extremely close to the starting point of regeneration, although I do not know if they realise this yet. As a resultant, this could be the first treatment based on the SOD1 mouse that could actually be of some benefit to sALS sufferers.

What are we up against?

Using gene expression profiling comparing ALS cases and controls, 2113 genes were differentially expressed with 1,772 up regulated and 341down regulated in patients versus controls. In primary lateral sclerosis there are 2488 differentially expressed genes.
www.mndassociation.org/research/for_researches/international_symposium/20th_international_symposium_on_alsmnd/abstract_book_2009.html See article P120 on page 125. There should be fewer pathways involved in fALS so I would predict that there will be less differentially expressed genes in fALS.
It is also known that some genetic alterations can affect more than one protein. So even if 10% have been trialled or suggested as possible treatments, there may still be over 1,900 or 2,240 possibilities that have not even been suggested yet, and that is not even considering all the different phenotypes of ALS. Without a plausible theory that answers “multiple” questions, everything else is just hit and miss.

My suggested verification is very simple and inexpensive, but the actual cell type involved in the chronic muscular injury may have to be carefully selected and a couple of different cell types may have to be trialled. There is a different cell type in muscles that should result in type 2 diabetes. This could be run concurrently with any ALS trial. I point this out as there is one possible treatment that could treat ALS, type 2 diabetes and a small number of cancers. This increases the possible market, and could overcome pharmaceutical companies’ reluctance to invest huge sums of money in ALS treatments because of the relatively small number of patients with ALS.
For more information on the connection to type 2 diabetes see my recent post on the “Forums choice program at ALS TDI > Metformin. http://www.als.net/forum/Default.aspx?g=posts&t=45922&p=5 The references in this post help explain the sALS pathways.

Here are just a few examples of what you can expect if you explore this theory:
When looking for confirmation of the “Chronic regeneration failure” theory, you must relate results with the first stage of regeneration using only the beta/mesoderm lineage.
Misfolding: The answer why cells have altered folding patterns is explained by the fact that most somatic cells fold to threonine residues whereas during the first stage of regeneration or repair, they will be phosphorylated on serine residues. This answers the perceived defect of Misfolding. This can be confirmed in the IGF-2 / GSK-3 pathway. (Most research looks at the loss of IGF-1 instead of the up regulation of IGF-2). Inactivated GSK-3β will fold to a serine 9 residue if tested in the beta/mesoderm lineage. This leads to an inhibition of beta catenin. Beta catenin is a subunit of cadherin protein complex and when inhibited it will result in a loss of M-cadherin allowing cell motility and new cell growth which is required during regeneration. The Wnt pathway will be stimulated. Also very relevant to ALS; reduced beta catenin signalling causes a decrease in neurogenesis. Inactivated GSK-3β leads to Tau folding to serine residues. A muscle cell will fold to a different serine residue compared to a neuron. Serine 202, 199, 396 and 404 are possibilities.

Inactivated GSK-3β leads to many things. It alters glucose metabolism from the normal insulin dependent glycogen synthase, to a cell lineage specific storage. In ALS, this will lead to altered metabolism in muscle cells, and with chronic regeneration, causes the increase in ROS or super oxide in the mitochondria, down regulates GAPDH and the last half of the glycolysis pathway, up regulates polyol, hexosamine, PKC, AGE, and pentose phosphate pathways. This leads to cellular specific glycosylation.IGF-2 to the pentose phosphate pathway covers most of the elusive ALS pathway. Just add the other side pathways activated by the cause, like the immune system etc, and the feedback of glycosylation back to cellular regeneration.
The above explanation and pathways are just a very quick and simplistic attempt to attract the attention of ALS TDI, so they can be considering the possibilities while I struggle to write up a very long comprehensive explanation on how everything fits the chronic regeneration failure theory. This theory is the result of eight years of painstaking private research. It is not just an “Oh, I had a bright idea moment”.

I haven’t explained the really important connection that links chronic muscle cell degeneration to the degeneration of neurons here. Many points of the explanation; such as why myelin is not produced to protect the axons; are in the aforementioned pathways, but the main reason comes from the starting point of cellular regeneration. This will be revealed to ALS TDI if they are interested enough to sign a formal agreement.

The best way to confirm the pathways involved in ALS is to study the first stage of repair in cells from the beta/mesoderm lineage, i.e. muscle cells. Not all ALS is caused by a chronic muscular injury so we need a marker for those with a physical injury. Once the ALS pathways are confirmed, many markers will become apparent. For now an unscientific marker would be sALS sufferers that suffer with unusually cold feet and poor circulation in the extremities. The reason for cold feet for those with a chronic physical injury is that in the first stage of cellular repair there is a presumption that there is a blood loss in the tissues that has to be urgently repaired. To do this the body starts the extrinsic/primary pathway in the coagulation cascade where calcium is required for many of the different reactions. When there is blood loss; even when it is only of a micro nature; the body restricts the capillaries or arterioles in the extremities to maintain sufficient blood pressure to the main organs. It does this by up regulating endothelin 1, a vasoconstrictor, and if the injury is chronic, the small capillaries remain constricted, causing poor blood flow and hypertension, and as a result, cold feet with a bruised look. Endothelin 1 and up regulated PAI-1 would be a more scientific marker, and a very difficult to determine marker would be early NMJ failure.
You could fill over half a page with all the things that require increased intracellular calcium during the first stage of repair. Calcitriol, the active form of vitamin D is known as a controller of homeostasis of calcium and phosphate. Calcitriol is down regulated and CYP24A1 is up regulated during cellular regeneration. This causes loss of homeostasis of calcium in order to allow regeneration. When repair is chronic a large build up of calcium in the tissue can then occur over time in the injured area. The only benefit of this is that once the build up occurs, it can be seen on a T2 weighted index MRI scan. If the sALS patient has a good idea where the chronic injury is situated, and it is confirmed by an MRI scan, it may be possible to actually cure ALS with an operation, as long as it can fix the injury. I know this idea is hard to believe, but I have conducted a private survey using the same thinking on type 2 diabetes patients which indicated that at least 30-40% of the patients had the potential to be cured by an operation. Familial ALS will not be helped with an operation but some sALS caused by various other insults may be helped and others will not.

Here is a challenge!

If you would like to play a positive part in evaluating this theory, choose any one point mentioned above and try to either prove or disprove the statement. The commonest method used by researchers is to try to disprove a theory to determine if it has any merit.

David Hicks.
Knowing the cause is nothing, understanding the cause is everything.

---

David Hicks.

Dave J,

The basics of your thinking are in tune with mine, but I have some twists (which still need proving) in my proposal. Either one of us could be correct. I would like to use your points and explain how they would fit in with the “Chronic regeneration failure theory”.

1. Injury starts in the muscle, and continued use of the muscle caused by normal movement creates a chronic injury. This injury has to involve bleeding in the muscle tissue so the vascular injury and the tissue injury are one. Chronic loss of blood is very important in the progression to disease. The chronic injury then causes the slow death of motor neurons which can be explained, but not here.

2. This is more a case of antigen presentation rather than antibody presentation. Antigen presenting cells; which are dendritic cells; such as monocyte/macrophage cells initially engulf the injured muscle cells, break them down and present them to a T helper cell to determine if there is any toxin, mutagen, virus or bacteria etc in the injured cells. CD40L is involved at this point.

3. The monocyte/macrophages normal role is also to present “self” as well as parts of injured or dead tissue so they will engulf healthy tissue as well as injured tissue as long as the injury continues. This is not present medical thinking, but I am proposing that dendritic cells also initiate the cellular “recipe” required to regenerate new cells.

4. Initially the injury is in one area in the muscle and it takes a few years before enough neurons die and ALS symptoms start to appear.

5. If this injury fixes itself early or an operation can stop the chronisity, (that may not be a word), ALS will not eventuate.

6. The muscle injury does not kill off neurons; it stops the regeneration of new neurons and hence causes a regeneration failure. This is why it is a progressive disease. All cells are continuously being replaced, usually by mitosis, but if large numbers of cells need replacing, regeneration is necessary. At first, cells are replaced by mitosis until telomeres shorten to such an extent they can no longer divide. These cells are then not replaced and the number of dead cells increases, requiring regeneration. Because the motor neuron regeneration process is switched off, neurons cannot be regenerated. The muscle injury is localized to one area, but as the death of neurons is the result of regeneration failure, motor neurons can be affected anywhere in the body. The initial muscle injury would probably be located near the area of the first symptoms of sALS.

An operation that can stop the muscle injury will “stop the progression of sALS”. Present medical knowledge indicate that a long axon will probably require over a year to regrow so the muscles will not instantly start working again, and there is sure to be a period of physio required after that. Hopefully, new knowledge of the “recipe” for the regeneration of neurons will allow a reduction in time to regrow the axon. If the neuron is fully dead, it may not be able to be replaced at this stage until further advances are made.

David Hicks.

Knowing the cause is nothing, understanding the cause is everything.

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David Hicks.