Joint developments in genetics and tissue analysis methods by immunohistochemistry have shown that the disease was related to abnormal protein deposition in the central nervous system.
In most cases of ALS, the TDP43 protein, normally contained in the nucleus of neurons, accumulates in the cytoplasm. The same protein is identified in frontotemporal lobar degeneration (LFT) lesions suggesting mechanisms common to both diseases.
In hereditary SLAs, the accumulated protein is not always TDP43 but can be the one produced by the mutated gene: for example the SOD-1 protein in mutations of the SOD-1 gene, the FUS protein in gene mutations FUS. TDP-43 and FUS are RNA binding proteins, which regulate different stages of RNA metabolism. The mechanisms by which accumulated proteins are toxic to the nervous system are not yet fully known.