Abnormal TDP-43 and FUS proteins in muscles of sporadic IBM: similarities in a TARDBP-linked ALS patient

Abnormal protein deposits are observed in the cytoplasm of sporadic inclusion body myositis (s-IBM) muscle. A number of proteins known to be included in s-IBM aggregates have also been described in various neurodegenerative diseases, including ubiquitin, β amyloid peptide, α -synuclein, phosphorylated τ and TAR DNA-binding protein (TDP-43). In the central nervous system (CNS), TDP-43 aggregates are characteristic of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive neuronal inclusions. Numerous dominant mutations in the TARDBP gene encoding TDP-43 protein have been reported in ALS cases, demonstrating that TDP-43 abnormalities could directly trigger neurodegeneration. The recent discovery of mutations in the gene encoding Fused in Sarcoma (FUS) protein, which shares functional and structural homology with TDP-43, has strengthened the prominence of gene expression-mediating proteins in ALS pathogenesis. Whether muscle TDP-43 aggregates observed in s-IBM are just trashed protein, or whether they are pathogenic, particularly trough RNA metabolism disturbances, remains unknown. We hypothesised that FUS protein could be altered in TDP-43 positive muscles of s-IBM. For this purpose, we investigated the protein muscle expression of TDP-43 and FUS in s-IBM compared to sporadic amyotrophic lateral sclerosis (SALS) patients (including one patient with TARDBP gene mutation) and controls. We report abnormal FUS and TDP-43 fragments in s-IBM and TARDBP -linked disease. Five patients with s-IBM, five patients with …