TDP-43 levels in the brain tissue of ALS cases with and without C9ORF72 or ATXN2 gene expansions

Neurology. 2019 Nov 5;93(19):e1748-e1755. doi: 10.1212/WNL.0000000000008439. Epub 2019 Oct 16.


Objective: 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 ATXN2 or C9ORF72 genes.

Methods: 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 ATXN2 or C9ORF72 genes and sporadic disease and 10 controls.

Results: Significantly greater levels of phosphorylated TDP-43 were identified in the motor cortex of cases with ALS with C9ORF72 expansions, and significantly greater amounts of phosphorylated TDP-43 were found in the spinal cord of cases with ALS with intermediate ATXN2 expansions. In contrast, however, similar levels of nonphosphorylated TDP-43 were found in all 3 regions between ALS groups.

Conclusion: 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 C9ORF72 or ATXN2 expansions and are of relevance to therapeutic research aimed at reducing pathologic TDP-43 in all or a subset of patients with ALS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism*
  • Ataxin-2 / genetics*
  • Brain / metabolism*
  • C9orf72 Protein / genetics*
  • Case-Control Studies
  • Cerebellar Vermis / metabolism
  • DNA Repeat Expansion
  • DNA-Binding Proteins / metabolism*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Motor Cortex / metabolism
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Spinal Cord / metabolism*


  • ATXN2 protein, human
  • Ataxin-2
  • C9orf72 Protein
  • C9orf72 protein, human
  • DNA-Binding Proteins
  • TARDBP protein, human