I can tell you after being in neurology for 50 years that back in the day every microscopic inclusion found in neurologic disease was thought to be causative. This was certainly true for the senile plaque of Alzheimer’s disease and the Lewy body of Parkinsonism. Interestingly, the protein inclusions in ALS weren’t noticed for decades.
However there are 3 possible explanations for any microscopic change seen in any disease. The first is that they are causative (the initial assumption). The second is that they are a pile of spent bullets, which the neuron uses to defend itself against the real killer. The third is they are tombstones, the final emanations of a dying cell, a marker for the cause of death rather than the cause itself.
An earlier post concerned work that implied that the visible aggregates of alpha-synuclein in Parkinson’s disease were protective rather than destructive — https://luysii.wordpress.com/2018/01/07/are-the-inclusions-found-in-neurologic-disease-attempts-at-defense-rather-then-the-cause/.
Comes now Proc. Natl. Acad. Sci. vol. 115 pp. 4661 – 4665 ’18 on Superoxide Dismutase 1 (SOD1) and ALS. Familial ALS is fortunately less common than the sporadic form (under 10% in my experience). Mutations in SOD1 are found in the familial form. The protein contains 153 amino acids, and as 6/16 160 different mutations in SOD1 have been found. Since each codon can contain only 3 mutations from the wild type, this implies that, at a minimum, 53/153 codons of the protein have been mutated causing the disease. Sadly, there is no general agreement on what the mutations actually do — impair SOD1 function, produce a new SOD1 function, cause SOD1 to bind to something else modifying that function etc. etc. A search on Google Scholar for SOD1 and ALS produced 28,000 hits.
SOD1 exists as a soluble trimer of proteins or the fibrillar aggregate. Knowing the structure of the trimer, the authors produced mutants which stabilized the trimer (Glycine 147 –> Proline) making aggregate formation less likely and two mutations (Asparagine 53 –> Isoleucine, and Aspartic acid 101 –> Isoleucine) which destabilized the trimer making aggregate formation more likely. Then they threw the various mutant proteins at neuroblastoma cells and looked for toxicity.
The trimer stabilizing mutant (Glycine 147 –> Proline) was toxic and the destabilizing mutants (Asparagine 53 –> Isoleucine, and Aspartic acid 101 –> Isoleucine) actually improved survival of the cells. The trimer stabilizing mutant was actually more toxic to the cells than two naturally occurring SOD1 mutants which cause ALS in people (Alanine 4 –> Valine, Glycine 93 –> Alanine). Clearly with these two something steric is going on.
So, in this experimental system at least, the aggregate is protective and what you can’t see (microscopically) is what kills cells.
Chemiotics II 