While not a scientist, I read many scientific articles about ALS (there are ~15,000 per year), most are useless from the perspective of someone interested in a cure, but I think this one may be onto something.
This work broadens the classical TDP-43 narrative; traditionally, TDP-43 aggregates are viewed as problematic because they are localized in the cytosol, not the nucleus. Here, the narrative is that it is problematic because it accumulates in the neuro-muscular junction.
The mechanistic explanation (which is very rare in ALS publications) is that as TDP-43 binds thousands of mRNAs, it suppresses their translation when overabundant, and in motor neurons, which are incredibly long, translation must happen at their extremities. Hence, the neuro-muscular junction becomes dysfunctional.
As for a potential treatment, targeting skeletal muscle rather than the CNS is more accessible and safer.
This work broadens the classical TDP-43 narrative; traditionally, TDP-43 aggregates are viewed as problematic because they are localized in the cytosol, not the nucleus. Here, the narrative is that it is problematic because it accumulates in the neuro-muscular junction.
The mechanistic explanation (which is very rare in ALS publications) is that as TDP-43 binds thousands of mRNAs, it suppresses their translation when overabundant, and in motor neurons, which are incredibly long, translation must happen at their extremities. Hence, the neuro-muscular junction becomes dysfunctional.
As for a potential treatment, targeting skeletal muscle rather than the CNS is more accessible and safer.
https://www.nature.com/articles/s41593-025-02062-6