Some technical pointers for newbies and I stress this is only my point of view - the type of ALS you have a an individual should in theory dictate the type of therapy you should be looking at.
In other words there is a difference between known genetic types of ALS, the main ones being SOD1 and TDP-43 mutations. Some substances (drugs, suppliments etc) work better for SOD1 dysfunction and some work better for TDP-43 dysfunction.
FUS/TLS mutation is another sub type of ALS with mental decline in ALS patients.
As most of us are sporadic ALS we will not know what type we are?
So the following may indicate or point to what type of ALS you have and possible enable you to slectively target your home grown therapy.
Bulbar onset seems to be mostly TDP-43 dysfunction but this is not 100% true but near enough and notice below that no FUS/TLS mutations were found in a survey of 293 patients with sporadic ALS.
Common pathways for all types seem to be immune/inflammation modulation but in SOD dysfunction this may be a driver of progression speed.
Not proven or seen, by myself, in TDP-43 so far but papers are sparse on TDP-43 dysfunction immune modulation and whether the immune system is a driver of illness progression.
This also has relevance when looking at any technical paper if you think you know what sub type you are.
You will see references in technical papers to the following so some explanation is required:
PALS = people with ALS
SALS = sporadic ALS =no known cause of ALS and doesn't run in families. About 90% of ALS is of this type.
FALS = familiar ALS = runs in families and usually caused by a genetic mutation with (not always) an aging factor.
From the TDP-43 type ALS thread:
http://www.als.net/forum/yaf_postst50601_TDP43-type-ALS.aspxMutations 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.
Abnormal TDP-43 is not present in cases of ALS with SOD1 mutations, which suggests that SOD1-related ALS and sporadic ALS are not caused by the same disease mechanisms.
However, abnormal TDP-43 is present in familial cases of ALS that lack SOD1 mutations, which suggests some familial and sporadic ALS cases are caused by similar mechanisms.
Recent advances in research have identified an ubiquinated protein that is commonly found in the majority of ALS cases.
In healthy nerve cells this protein, called TDP-43, is typically localized to the nucleus.
The nucleus is where the cell stores the information required to make proteins needed for normal cell function.
However, in affected nerve cells, TDP-43 is only found in the cytoplasm.
The cytoplasm is located outside of the nucleus and is the primary site for chemical activity in the cell.
Additionally, biochemical studies have shown that the accumulated TDP-43 located in the affected nerve cells contain abnormal variants of the protein.
The accumulation of abnormal TDP-43 in this area of the cell is speculated to cause a loss in cellular function (due to the absence of normal TDP-43 in the nucleus), thereby impairing the viability of the affected nerve cells.
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The researchers detected the clumps of TDP-43 in the brains of all cases except the SOD1 cases, suggesting that most forms of ALS were driven by TDP-43 abnormalities, while SOD1 was relevant only in rare cases.
If so, this finding would have major implications for ALS research, since the standard tool for drug testing in ALS since the mid 1990s has been a transgenic mouse with mutant SOD1—a “model” assumed to share most of its disease pathways with ordinary ALS
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No FUS/TLS mutations were found in a survey of 293 patients with sporadic ALS.
2. Importantly, TDP-43-positive inclusions are absent in ALS patients with FUS/TLS mutations, implying that neurodegenerative processes driven by FUS/TLS mutations are independent of TDP-43 aggregation
3. A considerable proportion of patients with SALS harboured mutations in major ALS genes. This result has relevant implications in clinical practice, namely in genetic counselling. The detection of double mutations in 2 patients raises the hypothesis that multiple mutations model may explain genetic architecture of SALS.
Clinical comparison of SOD1, TARDBP, FUS and other familial ALS patients (with no mutation in the screened genes) revealed differences in site of onset (predominantly lower limbs for SOD1 and upper limbs for TARDBP mutations), age of onset (younger with FUS mutations), and in lifespan (shorter for FUS carriers).
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This possibly indicates that the chances of those with bulbar onset are not SOD1 mutants but probable TDP-43.
Note it just means the odds are better that bulbar onset is not SOD1 mutant type.
Bulbar onset has been claimed to be rare among patients with SOD1 mutations but has been reported (Table 2).
While many patients with SOD1 mutations reportedly are clinically identical to patients without SOD1 mutations, a predominantly lower motor neuron pattern is the rule for patients with a SOD1 mutation.
No case with predominantly upper motor neuron (UMN) features have been reported for SOD1 mutants.
www.marionegri.it/mn/it/docs/aggiornamento/news/..............................................
Background: Most ALS cases are characterized with TDP-43(+), ubiquitin(+) inclusions in their diseased spinal cord motor neurons.
Results: Mice with targeted depletion of TDP-43 expression in the spinal cord motor neurons developed a range of ALS-like phenotypes.
Conclusion: TDP-43 is essential for the survival and functioning of the mammalian spinal cord motor neurons.
Significance: Loss-of-TDP-43 function could be one major cause for neurodegeneration in ALS with TDP-43 proteinopathies.
This study not only establishes an important role of TDP-43 in the long term survival and functioning of the mammalian spinal cord motor neurons, but it also establishes that loss-of-TDP-43 function could be one major cause for neurodegeneration in ALS with TDP-43 proteinopathies.
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TDP-43 continuously shuttles between the nucleus and cytoplasm, a process partially regulated by nuclear localization signal (NLS) and nuclear export signal (NES) motifs.
Restricting TDP-43 from entering the nucleus by changing the NLS motif in cell leads to cytoplasmic TDP-43 aggregates, changes in the solubility of TDP-43 and sequestration of endogenous TDP-43, thereby leading to a depletion of nuclear TDP-43
Thus, perturbation of the normal shuttling of TDP-43 between nucleus and cytoplasm leads to the formation of cytoplasmic inclusions and loss of nuclear TDP-43
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TDP-43 helps ensure proteins are produced appropriately by regulating the processing and translation of RNAs. But in over 90% of people with ALS, TDP-43 builds up in the cytoplasm of cells of the brain and spinal cord. The role of TDP-43 in ALS however remains controversial.
The team found that nearly one third of all genes in the mouse brain may be regulated at least in part by TDP-43. And, within the center of the brain, more than 1000 RNAs required TDP-43 for appropriate assembly or stability.
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To determine the effects of misplaced TDP-43 on the viability of neurons, the researchers made transgenic mice expressing human mutated TDP-43 in the cytoplasm and compared them to mice expressing normal human TDP-43 in the nucleus of nerve cells.
Expression of either human TDP-43 led to neuron loss in vulnerable forebrain regions; degeneration of part of the spinal cord tract; and muscle spasms in the mice.
These effects recapitulate key aspects of FTLD and a subtype of ALS known as primary lateral sclerosis.
The JCI study showed that a dramatic loss of function causes nerve-cell death because normal mouse TDP-43 is eliminated when human mutated TDP-43 genes are put into the mice.
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Neurodegeneration in the mouse neurons expressing TDP-43 -- both the normal and mutated human versions -- was accompanied by a dramatic downregulation of the TDP-43 protein mice are born with.
What’s more, mice expressing the mutated human TDP-43 exhibited profound changes in gene expression in neurons of the brain’s cortex.
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A recent study has shown that TDP-43 protein can be detected in blood samples and that levels of the protein are elevated in some patients with Alzheimer disease and FTD.
Two other small studies in Germany and Japan detected TDP-43 in cerebral spinal fluid (CSF) and found increased levels of TDP-43 in some patients with sporadic ALS.
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Possible linkage in pathology between SOD1 and TDP-43
PALS with a SOD1 defect have a build up of mutant SOD1 in their motor neurones, something which looks to be detrimental to neurone health.
In these people it's easy to visualise why a drug that removes SOD1 might be beneficial.
For the 98% of PALS with no SOD1 defect there is no build up of SOD1 but there are TDP-43 aggregates. A recent paper indicated that excess TDP-43 downregulates SOD1...
The inverse correlation between increased TDP-43 and decreased SOD1 expression suggests a repressor role for TDP-43.
Such a repressor function of TDP-43 on select gene targets has been observed by others.
The validation of 5 out of 11 target genes from the TDP-43 linked protein interaction network as regulators of SOD1 expression (Figure S4 A, B) adds further credence to the importance of the network (Figure 4).
The current finding that TDP-43 regulates SOD1 is also consistent with a recent micro array study, where a modest increase in SOD1 mRNA levels was observed upon TDP knockdown'
This could be interpreted as the problem being as much the lack of SOD1 as it is the build up of TDP-43
The point being that PALS with no SOD1 defect might not want to take a compound that lowers SOD1 until there is a better understanding as to what's causing the disease.
Into the heart, an air that kills, from yon far country blows.
What are those blue remembered hills, what sphires what farms are those.
That is the land of lost content,I see it shining plain,
The happy highways where I went and cannot come again