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Background: TAR DNA-binding protein-43 (TDP-43) proteinopathies are classified based upon the extent of modified TDP-43 and include a growing number of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with ubiquitin immunoreactive, tau-negative inclusions (FTLD-U) and FTLD with motor neuron disease (FTLD-MND). Objective: The purpose of the study was to examine whether proteolytic modifications of TDP-43 are a relevant finding in Parkinson’s disease (PD) and dementia with Lewy Bodies (DLB). Methods: A novel site-directed caspase-cleavage antibody, termed TDP caspase-cleavage product antibody (TDPccp), was utilized based upon a known caspase-3 cleavage consensus site within TDP-43 at position 219. Results: Application of this antibody to postmortem brain sections from PD and DLB revealed the presence of caspase-cleaved TDP-43 in Lewy bodies and Hirano bodies in all cases examined. Co-localization of TDPccp with an antibody to alpha-synuclein (α-Syn), which served as a general marker for Lewy bodies, was evident within the substantia nigra in both alpha-synucleinopathies. Interestingly, the TDPccp antibody detected a greater number of Lewy bodies in PD and DLB compared to the α-Syn antibody. In addition, a semi-quantitative analysis in both diseases confirmed this finding by indicating that the percent of caspase-cleaved TDP-43 single-labeled Lewy bodies was approximately twice the percent that of α-Syn labeling (in DLB 13.4% vs. 5.5%, while in PD 34.6% vs. 17.6%, respectively). Conclusion: Collectively, these data have identified caspase-cleaved TDP-43 as a primary component of Lewy and Hirano bodies in PD and DLB, and suggest the TDPccp antibody is an effective marker for the detection of Lewy bodies in these neurodegenerative diseases.

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This is an author-produced, peer-reviewed version of this article. The final, definitive version of this document can be found online at Neurodegenerative Diseases published by Karger. Copyright restrictions may apply. DOI: 10.1159/000287952

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