Repeat expansions contribute to TDP-43 pathologic heterogeneity in ALS

Although the pathogenesis of amyotrophic lateral sclerosis (ALS) is far from being elucidated, a central role is played by the aggregation of TAR DNA binding protein 43 (TDP-43) in the brain and the spinal cord of patients with ALS, as shown by postmortem neuropathologic studies.1,2 Accompanying the great clinical and genetic heterogeneity of this disease, heterogeneous TDP-43 pathology has also been described. Patients with ALS with a C9orf72 repeat expansion, the most common pathogenic genetic risk factor,3 have more extensive pathologic TDP-43 deposition in extramotor brain regions relative to patients with ALS without a C9orf72 repeat expansion.4 While intermediate-length polyglutamine repeat expansions in ataxin 2 ( ATXN2 ) are associated with increased genetic risk for ALS and the morphology of TDP-43 pathologic inclusions in ATXN2 appears to be different from sporadic forms of ALS,5 the levels of phosphorylated and nonphosphorylated TDP-43 have not been previously reported. By investigating the regional deposition levels of TDP-43 (posttranslationally modified or not) in patients with ALS with C9orf72 or ATXN2 repeat expansions compared with cases of sporadic ALS, we may able to uncover insights about pathogenic mechanisms contributing to ALS disease heterogeneity. This is an important topic because it may direct the choice of potential specific therapeutic strategies.