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ALS processes
Is this the third dimension our picture is currently missing?
Impairment of
HSR & UPR with age?
Cell energy
balance issues
Increased activity in SOD1 ALS - inactivation in TDP-43 ALS.
Ca2+ permeability
Calpain initiates TDP-43 mislocalization in the motor neurons expressing abnormally abundant Ca(2+)-permeable AMPA receptors. H
Needed in ER for several purposes.
Elevated homocysteine causes ER stress.
Does taurine help to alleviate ER stress?
Attachment of
cellular receptors
Protein misfolding
May cause protein misfolding.
May cause protein misfolding.
Does it stabilize SOD1?
Apparently a 1960s chemotherapy drug has the ability to prevent SOD1 aggregation and can break apart previous aggregates, all without interfering with the function of the normal protein. This should be quite interesting to see if that improves the proteomic breakdown and recycling of the misfolded protein which we know is ubiquitin-tagged for breakdown.
Normally in the nucleus; in ALS patient aggregates in the cytoplasm + clearage in the nucleus.

Non-mutated TDP-43 aggregates are found in all sALS and majority of non-SOD1 fALS.
Upregulation may reduce the packing of TDP-43 to stress granules and improve the degradation of misfolded TDP-43.
Takes misfolded proteins to lysosome, taking care they do not start aggregating.
Cell cycle
arrest (G1)
Dephosphorylates eIF-2a leading to dispersion of stress granules.
Stress granules are a temporary aggregation in cytosol, needed to collect superfluous RNA strains in stress situations when there is not enough energy for transcription. Usually they dissolve in about ten minutes but in ALS they seem to be permanent.
In amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration, TAR DNA binding protein 43 (TDP-43) accumulates in the cytoplasm of affected neurons and glia, where it associates with stress granules (SGs) and forms large inclusions. SGs form in response to cellular stress, including endoplasmic reticulum (ER) stress, which is induced in both familial and sporadic forms of ALS. Here we demonstrate that pharmacological induction of ER stress causes TDP-43 to accumulate in the cytoplasm, where TDP-43 also associates with SGs. Furthermore, treatment with salubrinal, an inhibitor of dephosphorylation of eukaryotic initiation factor 2-α, a key modulator of ER stress, potentiates ER stress-mediated SG formation. Inclusions of C-terminal fragment TDP-43, reminiscent of disease-pathology, form in close association with ER and Golgi compartments, further indicating the involvement of ER dysfunction in TDP-43-associated disease. Consistent with this notion, over-expression of ALS-linked mutant TDP-43, and to a lesser extent wildtype TDP-43, triggers several ER stress pathways in neuroblastoma cells. Similarly, we found an interaction between the ER chaperone protein disulphide isomerase and TDP-43 in transfected cell lysates and in the spinal cords of mutant A315T TDP-43 transgenic mice. This study provides evidence for ER stress as a pathogenic pathway in TDP-43-mediated disease.

Seems to associate with TDP-43 in the stress granules.
Main protein controlling stress granule dynamics.
Pathologic stabilization of stress granules could be the reason to loss of nuclear function of TDP-43 and consequent transcription of cryptic exons.
Release of
intracellular calcium
TDP-43 (43-kDa TAR DNA-binding domain protein) is a major constituent of ubiquitin-positive cytoplasmic aggregates present in neurons of patients with fronto-temporal lobular dementia and amyotrophic lateral sclerosis (ALS). The pathologic significance of TDP-43 aggregation is not known; however, dominant mutations in TDP-43 cause a subset of ALS cases, suggesting that misfolding and/or altered trafficking of TDP-43 is relevant to the disease process. Here, we show that the presenilin-binding protein ubiquilin 1 (UBQLN) plays a role in TDP-43 aggregation. TDP-43 interacted with UBQLN both in yeast and in vitro, and the carboxyl-terminal ubiquitin-associated domain of UBQLN was both necessary and sufficient for binding to polyubiquitylated forms of TDP-43. Overexpression of UBQLN recruited TDP-43 to detergent-resistant cytoplasmic aggregates that colocalized with the autophagosomal marker, LC3. UBQLN-dependent aggregation required the UBQLN UBA domain, was mediated by non-overlapping regions of TDP-43, and was abrogated by a mutation in UBQLN previously linked to Alzheimer disease. Four ALS-associated alleles of TDP-43 also coaggregated with UBQLN, and the extent of aggregation correlated with in vitro UBQLN binding affinity. Our findings suggest that UBQLN is a polyubiquitin-TDP-43 cochaperone that mediates the autophagosomal delivery and/or proteasome targeting of TDP-43 aggregates.
Is aggregation
Found in aggregates of both SOD1 and TDP-43.
The unfolded protein response (UPR) is a cellular stress response related to the endoplasmic reticulum. It is a stress response that has been found to be conserved between all mammalian species, as well as yeast and worm organisms. This article focuses on the mammalian response.

The UPR is activated in response to an accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum. In this scenario, the UPR has two primary aims: initially to restore normal function of the cell by halting protein translation and activating the signaling pathways that lead to increasing the production of molecular chaperones involved in protein folding. If these objectives are not achieved within a certain time lapse or the disruption is prolonged, the UPR aims towards apoptosis.

Sustained overactivation of the UPR has been implicated in prion diseases as well as several other neurodegenerative diseases, and inhibiting the UPR could become a treatment for those diseases.[1] Diseases subject to UPR inhibition include Creutzfeldt-Jakob disease, Alzheimer's disease, Parkinson's disease, and Huntington's disease.[2]
Hsp70 prevents Ire-1alpha activation.
By binding with the protein TRAF2, Ire1 activates a JNK signaling pathway14, at which point human procaspase 4 is believed to cause apoptosis by activating downstream caspases.
The protein encoded by this gene phosphorylates the alpha subunit of eukaryotic translation-initiation factor 2 (EIF2), leading to its inactivation, and thus to a rapid reduction of translational initiation and repression of global protein synthesis. It is a type I membrane protein located in the endoplasmic reticulum (ER), where it is induced by ER stress caused by malfolded proteins.[4]
Although PERK is recognised to produce a translational block, certain genes can bypass this block. An important example is that the proapoptotic protein CHOP (CCAAT/-enhancer-binding protein homologous protein), is upregulated downstream of the bZIP transcription factor ATF4 (activating transcription factor 4) and uniquely responsive to ER stress15. CHOP causes downregulation of the anti-apoptotic mitochondrial protein Bcl-216, favouring a pro-apoptotic drive at the mitochondria by proteins that cause mitochondrial damage, cytochrome c release and caspase 3 activation.
Halting of
protein translation
An anti-apoptotic protein that also controls e.g. mitochondrial dynamics.
Cell death
BAX inhibitors
Bax Inhibitor-1 (BI-1) is an evolutionary conserved endoplasmic reticulum (ER)-located protein that protects against ER stress-induced apoptosis.1 This function has been closely related to its ability to permeate Ca2+ from the ER2 and to lower the steady-state [Ca2+]ER.3 BI-1 may function as an H+/Ca2+-antiporter2 or Ca2+ channel.4 Recently, BI-1 was proposed as a negative regulator of autophagy through IRE1α.5 However, recent findings indicate that BI-1 may promote autophagy.6
Excess calcium in cytosol
Opening of
RyR on ER
Relevant genes
The MPTP was originally discovered by Haworth and Hunter [2] in 1979 and has been found to be involved in neurodegeneration, hepatotoxicity from Reye-related agents, cardiac necrosis and nervous and muscular dystrophies among other deleterious events inducing cell damage and death.[3][4][1][5]

MPT is one of the major causes of cell death in a variety of conditions. For example, it is key in neuronal cell death in excitotoxicity, in which overactivation of glutamate receptors causes excessive calcium entry into the cell.[6][7][8] MPT also appears to play a key role in damage caused by ischemia, as occurs in a heart attack and stroke.[9] However, research has shown that the MPT pore remains closed during ischemia, but opens once the tissues are reperfused with blood after the ischemic period,[10] playing a role in reperfusion injury.

MPT is also thought to underlie the cell death induced by Reye's syndrome, since chemicals that can cause the syndrome, like salicylate and valproate, cause MPT.[11] MPT may also play a role in mitochondrial autophagy.[11] Cells exposed to toxic amounts of Ca2+ ionophores also undergo MPT and death by necrosis
Cyclosporin A
Direct inhibition of the mitochondrial permeability transition pore: a possible mechanism responsible for anti-apoptotic effects of melatonin.
Andrabi SA1, Sayeed I, Siemen D, Wolf G, Horn TF.
Author information
Melatonin, the secretory product of the pineal gland, is known to be neuroprotective in cerebral ischemia, which is so far mostly attributed to its antioxidant properties. Here we show that melatonin directly inhibits the mitochondrial permeability transition pore (mtPTP). mtPTP contributes to the pathology of ischemia by releasing calcium and cytochrome c (cyt c) from mitochondria. Consistently, NMDA-induced calcium rises were diminished by melatonin in cultured mouse striatal neurons, similar to the pattern seen with cyclosporine A (CsA). When the mouse striatal neurons were subjected to oxygen-glucose deprivation (OGD), melatonin strongly prevented the OGD-induced loss of the mitochondrial membrane potential. To assess the direct effect of melatonin on the mtPTP activity at the single channel level, recordings from the inner mitochondrial membrane were obtained by a patch-clamp approach using rat liver mitoplasts. Melatonin strongly inhibited mtPTP currents in a dose-dependent manner with an IC50 of 0.8 microM. If melatonin is an inhibitor of the mtPTP, it should prevent mitochondrial cyt c release as seen in stroke models. Rats underwent middle cerebral artery occlusion (MCAO) for 2 h followed by reperfusion. Melatonin (10 mg/kg ip) or vehicle was given at the time of occlusion and at the time of reperfusion. Indeed, infarct area in the brain sections of melatonin-treated animals displayed a considerably decreased cyt c release along with less activation of caspase-3 and apoptotic DNA fragmentation. Melatonin treatment diminished the loss of neurons and decreased the infarct volume as compared with untreated MCAO rats. Our findings suggest that the direct inhibition of the mtPTP by melatonin may essentially contribute to its anti-apoptotic effects in transient brain ischemia.
Escape of
Ca & cytochrome c
Apparently nicotinamide countereffects the pore formation and cytochrome c release.
Caspase 9
Inhibited by Hsp70
Caspase 3
Binding of malate
Ca uptake
Does the sticking of misfolded SOD1 to the VDAC1 cause problems for mitochondria to get sufficient supply of ADP and pyruvate?
Acetyl-L-carnitine up-regulates expression of voltage-dependent anion channel in the rat brain.
Traina G1, Bernardi R, Rizzo M, Calvani M, Durante M, Brunelli M.
Author information
Acetyl-L-carnitine (ALC) exerts unique neuroprotective, neuromodulatory, and neurotrophic properties, which play an important role in counteracting various pathological processes, and have antioxidative properties, protecting cells against lipid peroxidation. In this study, suppression subtractive hybridization (SSH) method was applied for the generation of subtracted cDNA libraries and the subsequent identification of differentially expressed transcripts after treatment of rats with ALC. The technique generates an equalized representation of differentially expressed genes irrespective of their relative abundance and it is based on the construction of forward and reverse cDNA libraries that allow the identification of the genes that are regulated after ALC treatment. In the present paper, we report the identification of the gene of mitochondrial voltage-dependent anion channel (VDAC) protein which is positively modulated by the ALC treatment. VDAC is a small pore-forming protein of the mitochondrial outer membrane. It represents an interesting tool for Ca(2+) homeostasis, and it plays a central role in apoptosis. In addition, VDAC seems to have a relevant role in the synaptic plasticity.
Mitochondria are physically or functionally altered in many neurodegenerative diseases. This is the case for very rare neurodegenerative disorders as well as extremely common age-related ones such as Alzheimer’s disease and Parkinson’s disease. In some disorders very specific patterns of altered mitochondrial function or systemic mitochondrial dysfunction are demonstrable. This review classifies neurodegenerative diseases using mitochondrial dysfunction as a unifying feature, and in doing so defines a group of disorders called the neurodegenerative mitochondriopathies. It discusses what mitochondrial abnormalities have been identified in various neurodegenerative diseases, what is currently known about the mitochondria-neurodegeneration nexus, and speculates on the significance of mitochondrial function in some disorders not classically thought of as mitochondriopathies.

Keywords: Alzheimer’s disease, cybrid, mitochondria, mitochondriopathy, Parkinson’s disease, neurodegeneration, neurodegenerativ
DCA help?
DCA is supposed to shift the metabolism away from glycolysis and towards oxitative phosphorylation.
Release of
cytochrome c
Release of
cytochrome c
A hypothesis concerning a switch in cellular metabolism from pyruvate oxidation towards increased glycolysis (similar to Warburg effect in cancer cells). Presented in form of a discussion thread on the ALSTDI forum (requires registration on the said forum).
How could
this hypothesis
be tested?
Could biotin deficiency
play a role?
Participates in co2 and fatty acid processes.
Produced in the gut.
Supplementation helps in MS.

Worth a closer look.
It has been demonstrated that SOD, when misfolded, can aggregate in a manner analogous to that of amyloid proteins. 76 It has also been shown that these aggregates can form into pore-like structures, as assessed by atomic force microscopy. 77 These investigators used wild-type SOD and three pathogenic mutants to demonstrate that copper-induced oxidation of SOD could trigger aggregation into pore-like assemblies. Although a physiologic ion channel function has not been demonstrated in vitro for SOD aggregates, several physiologic studies in vivo suggest that pores may play a role in ALS pathogenesis. Vucic et al. 78 reported that muscle membrane potential was significantly reduced in familial ALS and spontaneous ALS. Their study suggested that persistent upregulated sodium conductances were associated with axonal degeneration in ALS. Pore formation by a nonselective cationic pore would likely cause both membrane depolarization and sodium conductance upregulation. Meehan et al. 79 also reported increased excitability of neurons that were depolarized in an SOD1 mutant mouse model of ALS. These studies showed that the motor neurons, when depolarized, sustained higher frequency firing and persistent inward currents which were activated at lower firing frequencies. Once again, these features would be consistent with the presence of a leakage current caused by a nonspecific pore tending to depolarize the membrane. Pieri et al. 80 reported an intrinsic hyperexcitability in the G93A mutant mouse cortical neurons. This was due to higher current density of a persistent sodium current.
If KCC2 is sufficiently reduced, GABA turns from inhibitory to excitatory.
Axonal transport
It may be worthwhile to have a look at cancer drugs.
The surprising finding that metabolic dysfunction in skeletal muscle can provoke motor neuron death 145 suggests that mitochondrial defects may be central to the retrograde neurodegeneration seen in mouse models of ALS.
Dynein /
Plasma level of H neurofilaments as a late-stage biomarker.
Cdk5 inhibition suppresses neurofilament phosphorylation
p38 MAP kinase
recycling faults
Multiple types of amyotrophic lateral sclerosis (ALS) harbored the same protein in pathologic formations, suggesting a common mechanism to target for therapy, investigators reported.

Studies of families affected by ALS demonstrated that mutations in UBQLN2, which encodes the ubiquitin-like protein ubiquilin 2, cause dominantly inherited, chromosome-X-linked ALS and ALS/dementia.

In addition, functional analysis showed that abnormalities in ubiquilin 2 appear to lead to defects in the protein degradation pathway, abnormal protein aggregation, and neurodegeneration, according to a research letter published online in Nature.

Moreover, the abnormal protein was found in patients with and without UBQLN2 mutations.
Do PALS with BiPAP
progress slower?
Baicalin, candesartan, furmeric acid esters
signaling faults
Muscle-specific overexpression of glial cell-derived neurotrophic factor (GDNF) in the G93A mouse preserves NMJs and improves motor neuron survival, 195 suggesting therapeutic potential of neurotrophic factor supplementation. However, deficits in neurotrophic factors are not seen in ALS patients; to the contrary, GDNF and CNTF are upregulated in muscle, CSF, and postmortem spinal cord from ALS patients. 196 - 199 The overabundance of these factors in symptomatic individuals suggests that their upregulation is part of a defensive response to existing pathology and is ultimately insufficient to halt disease progression. In line with this view, administration of CNTF 200 or brain-derived neurotrophic factor (BDNF) 201 showed no measurable benefit to ALS patients. It is possible that neurotrophic factors hold therapeutic potential if administered early and/or at intact NMJs (recapitulating the beneficial muscle-specific overexpression of GDNF reported by Li et al. 195 ), but such a requirement likely precludes their usefulness to ALS patients.
Nogo-A & Sema3A
Possibly occurs during retracting NMJ, prevents reinnervation.
The transition metal copper is essential for all aerobic organisms as it is required as cofactor in a diversity of cellular processes, including mitochondrial respiration, pigmentation, and iron homeostasis. Controversially, copper can be extremely toxic due to the formation of reactive oxygen species. Therefore, a homeostatic control of intracellular copper concentrations is needed, regulated by processes mediating copper import, distribution, storage and excretion. When one of these processes is distorted, copper-related diseases, characterized by either copper deficiency or accumulation, can develop. However, the exact mechanism of cellular copper excretion is at present incompletely understood. This is illustrated by a range of copper storage disorders with unknown etiology, in which patients are highly sensitive to hepatic copper accumulation when the dietary copper intake is enhanced. We focused primarily on the copper overload disorder copper toxicosis. In dogs, an exon 2 deletion of the COMMD1 gene is associated with this disease. In this thesis, we aimed to provide more insight into the role of COMMD1 in copper homeostasis. Since Commd1 knockout mice are embryonic lethal, and thus an appropriate genetic mouse model to study the role of Commd1 in copper toxicosis was lacking, we generated a hepatocyte-specific Commd1-deficient mouse model. Similar to a diversity of human copper overload disorders, Commd1 deficiency only resulted in a progressive copper accumulation (10- to 20-fold relative to controls) when the mice were fed a copper-rich diet. This suggests that Commd1 is a rate-limiting factor in hepatic copper excretion and genetically underlines the importance of Commd1 in normal hepatic copper excretion. Using a biochemical screen to identify novel protein interactions of COMMD1, we established an interaction between COMMD1 and ATP7A. ATP7A is a copper transporting P-type ATPase involved in copper transport along the gastro-intestinal tract and across the blood-brain barrier. Mutations in ATP7A are associated with the copper deficiency disorder of Menkes disease. COMMD1 was demonstrated to partially restore the impaired copper transporting function of ATP7A mutant proteins, and thus might be considered as a potential modifier of Menkes disease pathogenesis. In this same biochemical screen, we also identified an interaction between COMMD1 and the antioxidant SOD1. Mutations in SOD1 are associated with the neurodegenerative disorder Amyotrophic Lateral Sclerosis (ALS). COMMD1 was shown to impair the SOD1 scavenging function as result of abrogated SOD1 maturation. COMMD1 interfered with the process of SOD1 homodimerization resulting in enhanced cytotoxicity. Subsequently, we examined the effect of COMMD1 on ALS pathogenesis. A pathophysiological hallmark of ALS is the formation of large protein aggregates in the spinal cords of patients, leading to motoneuron damage. Strikingly, binding of COMMD1 to SOD1 mutants resulted in induced aggregate formation of mutant SOD1 proteins. This was accompanied by a marked increase in cellular damage. These findings therefore might suggest an important function for COMMD1 in ALS disease progression. In conclusion, the findings presented in this thesis contribute significantly to our understanding of COMMD1 function. Further, the Commd1-deficient mouse model will be of high value for future studies addressing the role of COMMD1 in copper homeostasis and other cellular processes.
A number of papers on the subject have been published By Dr Woodruff from University of Queensland.
Factor H
Speculation based on MD Jason Williams' theories - needs further looking into.
T cells
The inflammatory response in amyotrophic lateral sclerosis (ALS) is well documented but the underlying cellular mechanisms have not been fully elucidated. We report that microglia isolated from the mutant human superoxide dismutase 1 (SOD1) G93A transgenic mouse model of ALS have an increased response to the inflammatory stimulus, lipopolysaccharide. Cell surface area and F4/80 surface marker, both indicators of cell activation, are increased relative to transgenic wild-type human SOD1 microglia. Monocyte chemoattractant protein-1, known to be increased in ALS, is produced at three-fold higher levels by SOD1 G93A than by wild-type human SOD1 microglia, under activating conditions. This novel finding implicates ALS microglia as a source of the increased monocyte chemoattractant protein-1 levels detected in ALS patients and in the ALS mouse model.

Senses extra-cellular ligands; located in the cell outer membrane.

Associates with a protein called MD-2.
Hyaluronic acid
Inflammatory responses to triggers such as TNF-α involve macrophages with components that include miR-155. miR-155 is overexpressed in atopic dermatitis and contributes to chronic skin inflammation by increasing the proliferative response of T(H) cells through the downregulation of CTLA-4.[58] In Autoimmune disorders such as rheumatoid arthritis, miR-155 showed higher expression in patients' tissues and synovial fibroblasts.[2] In multiple sclerosis, increased expression of mir-155 has also been measured in peripheral and CNS-resident myeloid cells, including circulating blood monocytes and activated microglia.[59]
Lipopolysaccharides are the typical activator of the TLR-4 response in macrophages.

LPS is bound to the membrane to be recognized by TLR-4 by a co-receptor protein named CD-14.
Magnolia bark
Adaptive immune
T cells
-CD4+ / CD25+ / FoxP3
-reduced in PALS
-CD8+ and natural killer T cells
-increased in PALS
Pathways to
reduce inflammation
The neurotransmitter noradrenaline (NA) can provide neuroprotection against insults including inflammatory stimuli and excitotoxicity, which may involve paracrine effects of neighboring glial cells. Astrocytes express and secrete a variety of inflammatory and anti-inflammatory molecules; however, the effects of NA on astrocyte chemokine expression have not been well characterized.
Abnormally regulated
Discussion thread on the ALSTDI forum concerning the scientific aspects behind the weight loss in PALS. Requires registration on the said forum.
of antioxidants
Vit C
ATP7A is important for regulating copper levels in the body. This protein is found in most tissues, but it is absent from the liver. In the small intestine, the ATP7A protein helps control the absorption of copper from food. In other organs and tissues, the ATP7A protein has a dual role and shuttles between two locations within the cell. The protein normally resides in a cell structure called the Golgi apparatus, which modifies and transports newly produced enzymes and other proteins. Here, the ATP7A protein supplies copper to certain enzymes that are critical for the structure and function of bone, skin, hair, blood vessels, and the nervous system. If copper levels in the cell environment are elevated, however, the ATP7A protein moves to the cell membrane and eliminates excess copper from the cell.[citation needed

DO A SEARCH ON COMBINED ACTION WITH MISFOLDED SOD1! There could be something important to be found.
A hypothesis that ALS is driven by excess ammonia, caused by faults in the glycolysis process on one hand and the urea cycle on the other hand.
sodium benzoate
Associated genes
Antisense therapy is a form of treatment for genetic disorders or infections. When the genetic sequence of a particular gene is known to be causative of a particular disease, it is possible to synthesize a strand of nucleic acid (DNA, RNA or a chemical analogue) that will bind to the messenger RNA (mRNA) produced by that gene and inactivate it, effectively turning that gene "off". This is because mRNA has to be single stranded for it to be translated. Alternatively, the strand might be targeted to bind a splicing site on pre-mRNA and modify the exon content of an mRNA.[1]

This synthesized nucleic acid is termed an "anti-sense" oligonucleotide because its base sequence is complementary to the gene's messenger RNA (mRNA), which is called the "sense" sequence (so that a sense segment of mRNA " 5'-AAGGUC-3' " would be blocked by the anti-sense mRNA segment " 3'-UUCCAG-5' ").

Antisense drugs are being researched to treat a variety of diseases[2][3] such as cancers (including lung cancer, colorectal carcinoma, pancreatic carcinoma, malignant glioma and malignant melanoma), diabetes, Amyotrophic lateral sclerosis (ALS), Duchenne muscular dystrophy and diseases such as asthma, arthritis and pouchitis with an inflammatory component. As of 2014 two antisense drugs have been approved by the U.S. Food and Drug Administration (FDA), fomivirsen (marketed as Vitravene) as a treatment for cytomegalovirus retinitis and mipomersen (marketed as Kynamro) for homozygous familial hypercholesterolemia.
Mutations in the gene, called MATR3, were discovered in a family with members who were affected by ALS and dementia. The investigators subsequently identified similar mutations in an additional family, out of 108 familial cases tested. It was also found in one individual with sporadic ALS, out of 96 tested.

The authors showed that the MATR3 protein, called matrin, interacts with TDP-43, also a cause of ALS. TDP-43 aggregates inside cells in most people with ALS and mutant matrin was found to co-aggregate with it in the muscles of one person studied. Like TDP-43, matrin binds to DNA and to RNA and is normally involved in processing genetic messages.
TDP-43 mutations can cause ALS

Difference between TDP-43 and SOD1 mutations such that TDP-43 may be able to kill motor neurons direct but SOD1 mutants do not

Mutations in TDP-43 is a sub set of ALS different from SOD1 ALS

It looks like TDP-43 mutations on its own does not cause Frontotemporal lobar degeneration: FTLD

The C9ORF72 mutation is a major cause of familial frontotemporal dementia with TDP-43 pathology

More than 30 mutations in the TDP-43 gene have been identified in patients with familial and sporadic ALS.

ALS with a TDP-43 mutation is classified as ALS-10.
The clinical features of ALS-10 are quite similar to those of sporadic ALS.
Environmental factors
Kii peninsula
Lake Mascoma
According to R. Dunlop et al, BMAA can be incorporated into proteins instead of serine.
Old age
How about the mitochondrial genome? Will this degrade the mitochondrial function along with aging?
Vit D
Free thiamin and thiamin monophosphate levels were determined by an electrophoretic fluorometric micromethod in plasma and CSF of patients with amyotrophic lateral sclerosis (ALS), alcoholics, and controls. In plasma of patients with ALS as well as in plasma and CSF of alcholics, both thiamin and thiamin monophosphate concentrations were decreased so that the thiamin-thiamin monophosphate (T/TMP) ratio remained unchanged compared with that of controls. In CSF of patients with ALS, however, thiamin monophosphate values decreased much more than thiamin levels, so that the T/TMP ratio was significantly increased. The selective impairment of thiamin monophosphate production by nerve cells is likely to result from the reduction of the activity of thiamin pyrophosphatase, an enzyme synthetized and highly concentratd in the Golgi complex. Thiamin pyrophosphatase is known to diminish in ALS as well as in experimental motor neuronal degeneration or axotomy. Thus, the T/TMP ratio could be taken as an index of the impairment of neuronal protein synthesis in ALS.
Increased serum ferritin levels in amyotrophic lateral sclerosis (ALS) patients.
Goodall EF1, Haque MS, Morrison KE.
Author information
Iron misregulation promotes oxidative stress, a proposed pathological mechanism in neurodegenerative disease. The aim of this study was to evaluate serum iron metabolism indicators in 60 amyotrophic lateral sclerosis (ALS) patients and 44 age matched controls. Serum ferritin levels were significantly increased in ALS patients compared to controls (p < 0.001), while no differences in the levels of serum iron, transferrin, iron saturation or total iron binding capacity were found. Likewise no differences in C reactive protein (CRP) or caeruloplasmin were detected, suggesting that the elevated ferritin levels in ALS did not merely indicate an acute phase response. The increased ferritin level may reflect a general increase in stored iron or be a consequence of ongoing muscle degeneration.
Usually starts focally and then spreads from there on. Might be worthwhile to collect the data In a more systematic manner to possibly find out some indirect evidence of the intra-spinal processes.
Low pH in
High uric acid level seems to extend survival in men.
Low NRF2
Elevated in skeletal muscle but not in serum.
Upregulated in SOD1, downregulated in TDP-43 ALS.
Stuff that should
be trialled
Substances that
seem to help
A living document in the form of a discussion thread on the ALSTDI forum. Requires registration on the said forum.
Baicalin is a flavone, a type of flavonoid. It is found in several species in the genus Scutellaria, including Scutellaria lateriflora (blue skullcap). There are 10 mg/g baicalin in Scutellaria galericulata (common skullcap) leaves.[1] Baicalin is the glucuronide of baicalein.

It is a component of Chinese medicinal herb Huang-chin (Scutellaria baicalensis) and one of the chemical ingredients of Sho-Saiko-To, an herbal supplement.

Baicalin is a known prolyl endopeptidase inhibitor,[2] induces apoptosis in pancreatic cancer cells,[3] and affects the GABA receptors.[citation needed]
A supplement-based protocol developed by Dr. V. Tedone for his own daughter suffering from ALS.

The site has its own discussion forum for people experimenting with the protocol.
Oral Sodium Chlorite

After being dropped out of the NP001 trial - that he felt was helping - due to its termination, Ben Harris and a few other PALS reverse-engineered the stuff to be essentially sodium chlorite. Failing to have the opportunity to obtain SC intravenously, a formula has been described on the linked ALSTDI thread. Several PALS who have tried it, have reported a temporary relief on the UMN symptoms.

NOTE TO SELF: Could the effects be due to the same reason as DCA seems to work? DCA is mentioned as a residual product of water chlorination.
See note concerning Intra-cellular phenomena / ER stress
DIY trials
Waiting for
What happened to it?
Amyotroph Lateral Scler Frontotemporal Degener. 2013 Sep;14(5-6):397-405. doi: 10.3109/21678421.2013.764568. Epub 2013 Feb 19.
Randomized double-blind placebo-controlled trial of acetyl-L-carnitine for ALS.
Beghi E1, Pupillo E, Bonito V, Buzzi P, Caponnetto C, Chiò A, Corbo M, Giannini F, Inghilleri M, Bella VL, Logroscino G, Lorusso L, Lunetta C, Mazzini L, Messina P, Mora G, Perini M, Quadrelli ML, Silani V, Simone IL, Tremolizzo L; Italian ALS Study Group.
Collaborators (35)
Author information
Our objective was to assess the effects of acetyl-L-carnitine (ALC) with riluzole on disability and mortality of amyotrophic lateral sclerosis (ALS). Definite/probable ALS patients, 40-70 years of age, duration 6-24 months, self-sufficient (i.e. able to swallow, cut food/handle utensils, and walk), and with forced vital capacity (FVC) > 80% entered a pilot double-blind, placebo-controlled, parallel group trial and were followed for 48 weeks. ALC or placebo 3 g/day was added to riluzole 100 mg/day. Primary endpoint: number of patients no longer self-sufficient. Secondary endpoints: changes in ALSFRS-R, MRC, FVC and McGill Quality of Life (QoL) scores. Analysis was made in the intention-to-treat (ITT) and per-protocol (PP) population, completers and completers/compliers (i.e. taking > 75% of study drug). Forty-two patients received ALC and 40 placebo. In the ITT population, 34 (80.9%) patients receiving ALC and 39 (97.5%) receiving placebo became non-self-sufficient (p = 0.0296). In the PP analysis, percentages were 84.4 and 100.0% (p = 0.0538), respectively. Mean ALSFRS-R scores at 48 weeks were 33.6 (SD 10.4) and 27.6 (9.9) (p = 0.0388), respectively, and mean FVC scores 90.3 (32.6) and 58.6 (31.2) (p = 0.0158), respectively. Median survival was 45 months (ALC) and 22 months (placebo) (p = 0.0176). MRC, QoL and adverse events were similar. In conclusion, ALC may be effective, well-tolerated and safe in ALS. A pivotal phase III trial is needed.
J Neurol Sci. 2014 May 15;340(1-2):103-8. doi: 10.1016/j.jns.2014.03.005. Epub 2014 Mar 11.
Clinical and biological changes under treatment with lithium carbonate and valproic acid in sporadic amyotrophic lateral sclerosis.
Boll MC1, Bayliss L2, Vargas-Cañas S3, Burgos J4, Montes S5, Peñaloza-Solano G6, Rios C7, Alcaraz-Zubeldia M8.
Author information
The aim of this study was to evaluate the ability of lithium carbonate and valproate cotreatment to modify the survival rate and functional score of patients with definite sporadic amyotrophic lateral sclerosis (ALS). The clinical response of 18 enrolled patients was compared to the evolution of 31 ALS out-patients, carefully paired by age, gender, evolution rate and time of the disease, who never received treatment with lithium and/or valproate. The ALS functional rating scale, revised version (ALSFRS-R), was applied at baseline, 1month, and every 4months until the outcome (death or an adverse event). Biochemical markers, such as Cu/Zn superoxide dismutase and glutathione peroxidase activity, and reduced glutathione were assayed in plasma samples obtained at the baseline visit and after 5 and 9months of treatment. Our results showed that lithium and valproate cotreatment significantly increased survival (p=0.016), and this treatment also exerted neuroprotection in our patients because all three markers reached levels that were not significantly different from the matched samples of healthy donors. The trial stopped after 21months, when the sample was reduced to under two-thirds, due to the late adverse events of the treatment. The results call for large randomized clinical trials with the dual association, but at low doses to avoid adverse events.
Neurologist. 2012 Mar;18(2):92-5. doi: 10.1097/NRL.0b013e318247bb2d.
Amyotrophic lateral sclerosis and frontotemporal lobar degeneration in association with CADASIL.
Kim HJ1, Kim HY, Paek WK, Park A, Young Park M, Ki CS, Park HM, Kim SH.
Author information
Amyotrophic lateral sclerosis (ALS) can present with heterogeneous symptoms resulting from the involvement of multiple brain systems including extramotor cortical areas. Involvement of other brain areas can cause diverse clinical symptoms including cognitive impairment and extrapyramidal symptoms. We report the case of a 50-year-old woman with bulbar onset ALS and frontotemporal lobar degeneration (FTLD), confirmed as cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). The patient and her first-degree relatives harbored a mutation (R75P) in the NOTCH3 gene, indicative of vascular deficits. The details of this case add plausibility to the idea that ALS, FTLD, and CADASIL are different aspects of a spectrum of disorders with overlapping pathologic mechanisms.
See environmental factors / head injury
PD : To the best of our knowledge, this is the first report investigating the association between the C(−1562)T polymorphism in the MMP-9 gene and risk of PD, and the first study to confirm a positive association between the C(−1562)T polymorphism and risk of sALS. In our hospital-based case-control study, we demonstrated that the C(−1562)T polymorphism is a potential risk factor for both PD and sALS in the Han Chinese population of mainland China. In fact, we found that the polymorphism increases the risk of PD by approximately 2.3-fold and of sALS by nearly 2.2-fold.

These results contradict earlier observations in a Polish population involving 228 sALS patients [26]: in which 53 patients (23.2%) were identified as heterozygous and 7 (3.1%) as homozygous for the C(−1562)T polymorphism, while in control groups, 118 patients (27.6%) were identified as heterozygous and 6 (1.4%) as homozygous, and thus no significant association was observed between the C(−1562)T polymorphism of MMP-9 gene and risk of sALS (p = 0.47). This discrepancy may be due to small population, to ethnic differences, and/or to genetic background, and should be confirmed in cohorts in other countries and in other ethnicities from Asian countries.
Discussion thread on (the Deanna Protocol forum)
Pore formation?
Could the spirochetes cause pores that increase the ion leakage, making the ionic pumps work so hard as to deplete the cell energy reserves?
Caused by repeated expansions in the ATXN2 gene, a phenomenon also associated with increased risk for ALS.
Affected cell/
tissue types
Neuromuscular junction pathology occurs in ALS before the onset of overt clinical symptoms and motor neuron death (2, 24, 25, 26).

In mSOD1 muscles, increased total dismutase activity (41), high expression of uncoupling protein-3 (20) and other anabolic (22) and anti-oxidant enzymes (34, 50), mSOD1 aggregates (73), and muscle fiber atrophy (35) also precede significant motor neuron loss.

Interestingly, expressing a locally acting IGF-I isoform in mSOD1 muscles maintains neuromuscular junction integrity, delays motor neuron death, and extends lifespan (18).

It is therefore reasonable to suggest that ALS proceeds in a distal-to-proximal dying back pattern and that certain alterations of muscular origin could contribute to enhance axon vulnerability.
Skeletal muscle-restricted expression of human SOD1 causes motor neuron degeneration in transgenic mice
ozanezumab By GSK - phase III results due in 2015
Other glia
Sensory nerves
Specificity to
motor neurons
Low Ca
Abundance of
AMPA receptors
A separate mindmap exists behind the link.
If the degree of damage correlates with the metabolic need of the cell (need to follow up on this one), it could point to mitochondriopathic mechanisms.
Serotonin (5-HT) has been intimately linked with global regulation of motor behavior, local control of motoneuron excitability, functional recovery of spinal motoneurons as well as neuronal maturation and aging. Selective degeneration of motoneurons is the pathological hallmark of amyotrophic lateral sclerosis (ALS). Motoneurons that are preferentially affected in ALS are also densely innervated by 5-HT neurons (e.g., trigeminal, facial, ambiguus, and hypoglossal brainstem nuclei as well as ventral horn and motor cortex). Conversely, motoneuron groups that appear more resistant to the process of neurodegeneration in ALS (e.g., oculomotor, trochlear, and abducens nuclei) as well as the cerebellum receive only sparse 5-HT input. The glutamate excitotoxicity theory maintains that in ALS degeneration of motoneurons is caused by excessive glutamate neurotransmission, which is neurotoxic. Because of its facilitatory effects on glutaminergic motoneuron excitation, 5-HT may be pivotal to the pathogenesis and therapy of ALS. 5-HT levels as well as the concentrations 5-hydroxyindole acetic acid (5-HIAA), the major metabolite of 5-HT, are reduced in postmortem spinal cord tissue of ALS patients indicating decreased 5-HT release. Furthermore, cerebrospinal fluid levels of tryptophan, a precursor of 5-HT, are decreased in patients with ALS and plasma concentrations of tryptophan are also decreased with the lowest levels found in the most severely affected patients. In ALS progressive degeneration of 5-HT neurons would result in a compensatory increase in glutamate excitation of motoneurons. Additionally, because 5-HT, acting through presynaptic 5-HT1B receptors, inhibits glutamatergic synaptic transmission, lowered 5-HT activity would lead to increased synaptic glutamate release. Furthermore, 5-HT is a precursor of melatonin, which inhibits glutamate release and glutamate-induced neurotoxicity. Thus, progressive degeneration of 5-HT neurons affecting motoneuron activity constitutes the prime mover of the disease and its progression and treatment of ALS needs to be focused primarily on boosting 5-HT functions (e.g., pharmacologically via its precursors, reuptake inhibitors, selective 5-HT1A receptor agonists/5-HT2 receptor antagonists, and electrically through transcranial administration of AC pulsed picotesla electromagnetic fields) to prevent excessive glutamate activity in the motoneurons. In fact, 5HT1A and 5HT2 receptor agonists have been shown to prevent glutamate-induced neurotoxicity in primary cortical cell cultures and the 5-HT precursor 5-hydroxytryptophan (5-HTP) improved locomotor function and survival of transgenic SOD1 G93A mice, an animal model of ALS.
PMID: 16861147 [PubMed - indexed for MEDLINE]
Calcitonin gene-related peptide expression levels predict motor neuron vulnerability in the superoxide dismutase 1-G93A mouse model of amyotrophic lateral sclerosis.
Ringer C1, Weihe E, Schütz B.
Author information
In amyotrophic lateral sclerosis (ALS) some motor neurons degenerate while others survive. The molecular mechanisms underlying this selective vulnerability and resistance, respectively, are poorly understood. Since the neuropeptide, calcitonin gene-related peptide (CGRP), is expressed by many but not all motor neurons, we asked if motor neuron CGRP levels predict their vulnerability in the SOD1-G93A mouse model of ALS. In wild type mice three types of somatic motor neurons were distinguished based on their CGRP expression pattern, i.e. highCGRP, lowCGRP, and nonCGRP. Since motor nuclei III, IV and VI contained mostly nonCGRP motor neurons, they defined the oculomotor group. In comparison, the facial group (nuclei V, VII and XII) contained equal numbers of all three types, while the spinomedullary group (ambiguus nucleus and lumbar spinal cord) contained mainly highCGRP motor neurons. Analysis on the transcript level, and of mice lacking the αCGRP isoform, revealed that these group differences in CGRP expression were predominantly based on αCGRP. At disease end-stage in SOD1-G93A mice, group-specific extent of motor neuron loss correlated with CGRP expression as neurons with highCGRP were reduced by 80%, those with lowCGRP by 50%, and nonCGRP motor neurons were not significantly affected in all three groups. Finally, highCGRP motor neuron degeneration preceded lowCGRP motor neuron degeneration during disease progression. Our analysis revealed that the relative abundance of CGRP mRNA and immunoreactivity in motor neurons predicts their vulnerability. CGRP may be an autocrine or paracrine factor promoting motor neuron degeneration in this ALS model.
Researchers discover new clues about how amyotrophic lateral sclerosis develops
Johns Hopkins scientists say they have evidence from animal studies that a type of central nervous system cell other than motor neurons plays a fundamental role in the development of amyotrophic lateral sclerosis (ALS), a fatal degenerative disease. The discovery holds promise, they say, for identifying new targets for interrupting the disease's progress.

In a study described online in Nature Neuroscience, the researchers found that, in mice bred with a gene mutation that causes human ALS, dramatic changes occurred in oligodendrocytes—cells that create insulation for the nerves of the central nervous system—long before the first physical symptoms of the disease appeared. Oligodendrocytes located near motor neurons—cells that govern movement—died off at very high rates, and new ones regenerated in their place were inferior and unhealthy.
Spreading to
neighboring cells
VEGF promotes MMP-9.
Connection to
leaky gut?
In Phase 2 trials, Neuraltus' NP001 showed efficacy in patients with elevated LPS and IL-18.
neuronal Bax
Effect on
NMDA receptors
Discussion thread on Aberrant Astrocytes
Lowering the sodium-potassium ATPase level with the heart medicine digoxin has reduced the toxic quality of astrocytes in mice.
Mutant SOD1 astocytes are shown to secrete exosomes containing e.g. misfolded SOD1 and p97/VCP. These exosomes may subsequently be taken By neighboring neurones.
According to Cohen et al, NAC might prevent the misfolding-causing sulfide bonds from forming in TDP-43.
Misfolded TDP43 appears to spread through nervous system

The research team studied postmortem tissue samples collected from 76 people with ALS between 1985 and 2012. Focusing on 22 areas of the brain and spinal cord, they examined the location and concentration of inclusions containing toxic misfolded TDP43 protein in motor neurons and other central nervous system cells (including oligodendrocytes, a type of nervous system support cell).

The investigators noted that motor neurons containing TDP43-protein-containing inclusions showed signs of degeneration, corroborating findings from previous studies that link the presence of inclusions containing TDP43 protein with the degeneration and death of motor neurons.

Based on their study, the team speculates that misfolded TDP43 protein may spread through the ALS-affected brain and spinal cord in four stages. (The four stages did not correlate with the length of time a person had ALS.)

Stage 1: TDP43-protein-containing inclusions appear in nerve cells in the primary motor cortex, the part of the brain involved in planning and executing voluntary movement, as well as in nerve cells in the spinal cord and brainstem involved in swallowing and breathing.
Stage 2: Abnormal TDP43 protein spreads forward in the brain from the primary motor cortex and into brainstem areas that are associated with balance.
Stage 3: TDP43 protein inclusions are found further forward in a part of the brain called the frontal cortex, which is involved in thinking and planning, and areas near the primary motor cortex that are involved with sensation.
Stage 4: TDP43 protein inclusions spread to the brain's temporal lobe, which is involved in visual memory, processing of sensory input, language comprehension and emotion; and the hippocampus, which is involved in moving information from short- to long-term memory and in spatial navigation.
The researchers caution that their results are preliminary and additional studies currently under way will help map TDP43 protein distribution in ALS in more detail.
This is a central object, whose purpose is to serve as a structural basis for the Big Picture. I will try to collect the different relevant pathways here so that they can be used in e.g. Computer based data mining from the Internet.
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This html5 mind map file can be opened and edited with espresso Mind Map