Intracellular damage due to superoxide and misfold

Intracellular damage due to superoxide and misfolded (or demetallized or otherwise nonfunctional) SOD protein buildup are central to the majority of non-environmental ALS cases.

"Inflammation" can be a response, and not a cause. It may even be protective. Bonus: I have some unexpected time, Let Me Google That For You:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC...n_sectitle

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However, while the immune system can worsen disease, it is not the primary cause of disease since SOD1 mice deficient in B cells still get disease [123] and SOD1 mice without microglia have the same disease as those with normal microglia [124].

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Effects of Immune Therapies in Human Subjects with ALS

It is attractive to consider that modulation of the immune response will be a useful therapy in ALS. If neuroinflammation enhances disease activity, then control of neuroinflammation should be helpful [130] possibly by enhancing protective immunity [131].

So far there is little evidence in human subjects regarding the effects of enhancing protective immunity. There have been trials of immune suppression in ALS.

After treatment with minocycline, to reduce microglial activation, patients did worse [132]. This might suggest that microglial activation is beneficial in ALS . Total body irradiation and stem cell therapy were of no benefit in ALS [133]. Earlier attempts at immune therapy included treatment with intravenous immunoglobulin, which was of no benefit [134], with cyclophosphamide, which also was of no benefit [135] and with azathioprine and prednisone which was of no benefit [136].
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In diseases of autoimmune etiology such as multiple sclerosis, genome wide association studies show strong association with the MHC region and other immune genes [139] but this is not the case in ALS, although as already mentioned such genes are likely to influence the clinical course of ALS, rather than to be risks for acquiring ALS

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