TDP-43 levels in the brain tissue of ALS cases with and without <i>C9ORF72</i> or <i>ATXN2</i> gene expansions.

Abstract

To assess the amount of phosphorylated and nonphosphorylated TAR DNA-binding protein 43 (TDP-43) in the motor brain regions of cases of amyotrophic lateral sclerosis (ALS) with and without repeat expansions in the <i>ATXN2</i> or <i>C9ORF72</i> genes. The 45-kDa phosphorylated form of TDP-43 and 43-kDa nonphosphorylated form of TDP-43 were quantified by immunoblot in postmortem brain tissue from the motor cortex, spinal cord, and cerebellar vermis of 23 cases with ALS with repeat expansions in the <i>ATXN2</i> or <i>C9ORF72</i> genes and sporadic disease and 10 controls. Significantly greater levels of phosphorylated TDP-43 were identified in the motor cortex of cases with ALS with <i>C9ORF72</i> expansions, and significantly greater amounts of phosphorylated TDP-43 were found in the spinal cord of cases with ALS with intermediate <i>ATXN2</i> expansions. In contrast, however, similar levels of nonphosphorylated TDP-43 were found in all 3 regions between ALS groups. Despite its central role in the pathogenesis of ALS and the emergence of potential targets to modify its aggregation, TDP-43 levels have not been quantified in pathologically confirmed cases with ALS. The present results demonstrating significant differences in phosphorylated but not nonphosphorylated TDP-43 levels suggest that different posttranslational modifications are involved in the generation of greater pathologic TDP-43 levels identified here in our cohort of cases with genetic expansions. These findings are consistent with emerging studies implicating distinct pathomechanisms in the generation of pathologic TDP-43 in cases with ALS with <i>C9ORF72</i> or <i>ATXN2</i> expansions and are of relevance to therapeutic research aimed at reducing pathologic TDP-43 in all or a subset of patients with ALS.