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A Possible Cause

For some time it appeared that the inclusions found in the cytosol of neurons in degenerative disease were causing the disease, likely due to disruption of movement of organelles and proteins up and down the axons. But evidence is now suggesting that may not be the case. With TDP-43, it appears that depletion of it from the nucleus is the cause of disease. With SOD1, an unknown toxic gain of function is still theorized. However, a recent study reported that mutant SOD1 interacts with TDP-43 where normal SOD1 did not. Conflicting previous studies have found and not found misfolded SOD1 inclusions in the motor neuron cytoplasm of sporadic ALS patients, though a study using novel antibodies specific for denatured SOD1 reported small inclusions in all tested SALS patients. SOD1 is a highly complex protein and such are easily misfolded. Usually this is no problem as either chaperones refold the protein or intracellular autophagy destroys the errant protein. But age and stress can cause autophagy to decrease in effectiveness, possibly leaving errant proteins in the cell where they can do damage. So assuming that mutant SOD1 is present either by genetic mutation or routine misfolding not corrected or cleared by the cell, and assuming interactions between mutant SOD1 and TDP-43 where TDP-43 is depleted from the nucleus, it could be held that mutant or misfolded SOD1 causes disease through depletion of nuclear TDP-43.

Activation of the glial cells (astrocytes, microglia, etc.) is a driving force in ALS progression. Experiments where mutant SOD1 was limited solely to the glia demonstrated the ability to drive disease on their own. In the case of inherited forms of ALS where particular mutated genes produce mutated forms of proteins throughout the body it is easy to imagine disease spreading rapidly once initiated. But what drives the more common sporadic forms? A clue might be found by looking at prion disease. In fact, a recent study shows that Huntington’s Disease may very well spread this way, and it may be applicable to other neurodegenerative diseases. Indeed another study found that extracellular SOD1 can induce microglia to release pro-inflammatory cytokines and free radicals which promote motorneuron damage. A more recent study showed that introduced mutant SOD1 can induce disease. The biotech company Amorfix makes antibodies against extracellular mutant SOD1 and is now in trials to use these antibodies as a vaccine against ALS.

So with mutant or misfolded SOD1 we have multiple paths for disease as well as a likely pathway for spread of disease. Each of these questions are comparatively easy to test and seemingly easy to intercept in the extracellular space. I look forward to more studies to further illuminate these questions.

6 thoughts on “A Possible Cause”

  1. OK, so what does all this mean? My nephew has ALS and it came on fast and he is progressing. This vaccine against ALS, is it effective at slowing or stopping the progression of ALS? What are you looking at to halt or even reverse this horrible disease and why has it taken so long to bring attention to ALS? It angers me that there is so much money being spent to test anti-aging creams, but hardly any money going towards researching ALS. I would rather be all wrinkly than my nephew have Amyotropic Lateral Sclerosis. As a nurse, I know there is much more scientists can do in learning more about ALS and finding treatments and a miracle to halt and maybe even reverse the disease process. Come on people, get with the program and do something about ALS!!!!….

  2. The “vaccine” is in testing right now so there is no human data regarding efficacy. I have zero personal ability to conduct or influence research; i am just a PALS like your nephew. My purpose here is to find and attempt to analyze research for my fellow PALS and for the healthy people who may read this, impress upon them the complexity and urgency of this problem. The biggest problem we have is that due to the short survival time there is a relatively small living population of PALS (opposed to, say, MS which has a similar incidence but much longer survival). If more people were aware and the popular demand greater, more man-hours per year could be brought to bear to solve the mystery of this horror.

    Drug companies would also rather refactor existing molecules than do the research necessary to bring new ones from the bench. Again this is a popular demand issue.

  3. Thank you Eric for putting this together! Heady topic…but important to write. We do need a non scientific translation though…if we want to get our point across about proteinopathies.

  4. Michelle: In a nutshell, I propose that mutant or misfolded SOD1 protein forms an aggregate with TDP43 protein before it can be shuttled into the nucleus where it belongs. A breakdown or disruption of the cellular recycling system responsible for breaking down misfolded proteins results in an excess of bad SOD1 in the cell. Leakage of this misfolded protein outside of the cell and taken up by other cells seeds propagation of disease.

    This can neatly tie FALS and SALS together. But it’s only an untested theory cobbled together from basic science studies with very limited or no independent verification so keep that in mind.

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