Neuropathological Analysis

The first gene suspected in a familial form of ALS was SOD1, though it only accounts for a small percentage of familial forms of the disease. The following discoveries were the mutations in the genes for FUS ans TARDBP (encoding for TDP-43 protein). Neuropathological analysis led to the identification of insoluble cytoplasmic phosphorylated protein deposits in brain and spinal cord. TDP-43 is a broadly expressed and highly conserved protein with different functions in RNA metabolism, including RNA translation, splicing and transport. In physiological conditions, TDP-43 is located in de nucleus to apply its function, but a little amount can be found in the cytoplasm. In 2011, hexanucleotide repeat expansion mutations were discovered in a gene
Among these are TAF15 (TATA-binding protein associated factor 15) and another three ariants in a different gene (EWSR). EWSR, TAF15 and FUS constitute the FET protein family with deeply conserved RNA-binding motifs. These proteins participate in various cellular processes including transcription, pre-mRNA splicing and miRNA processing.
Mutations in MATR3 have also been identified in families with ALS and dementia. These proteins potentially play a role in transcription and they might also be involved in a form of distal myopathy (correlated with dysphonia and dysphagia). Modifications in this protein in the spinal cord were found in affected, as well as unaffected individuals. Nevertheless, a big epidemiological study organized on a sample of patients with ALS and FTD did not account for any case with this mutation, so the contribution of MATR3 to the familial forms of ALS seems to be
It is a source of spinal muscular atrophy (SMA). An investigation in sporadic ALS patients found an unexpected number of SMN1 copies (one or three rather than two); this occurred more frequently in cases than in controls. However, various studies have demonstrated that the typical deletions noticed in SMA do not take place in ALS patients.
There have also been some genes identified which are involved in cytoskeletal organization. Among them is a gene that encodes the heavy chain of neurofilament (NEFH), which has also been suspected in some cases of ALS. Mutations in PFN1 (encoding for Profilin-1) have also been found in some families with ALS. A few allelic variants in the PFN1, such as E117G, are thought to confer a low susceptibility to developing the