Cytoplasmic inclusions of TDP-43 in neurodegenerative diseases: A potential role for caspases

Troy T. Rohn

Department of Biology, Science/Nursing Building, Room 228, Boise State University, Boise, Idaho, USA.

Offprint requests to: Troy T. Rohn, Ph.D., Department of Biology, Science/Nursing Building, Room 228, Boise State University, Boise, Idaho, 83725, USA. e-mail: trohn@boisestate.edu


Summary. TAR DNA-binding protein-43 (TDP-43) proteinopathies are classified based upon the extent of modified TDP-43 inclusions and include a growing number of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with ubiquitin immunoreactive, tau negative inclusions (FTLD-U) and FTLD with motor neuron disease (FTLD-MND). In addition, TDP-43 inclusions have also been identified in a number of other neurodegenerative disorders including Alzheimer’s disease, corticobasal degeneration, Lewy body related diseases and Pick’s disease. Current understanding suggests that in these diseases, TDP-43 is relocated from the nucleus to the cytoplasm and sequestered into inclusions that contain modified TDP-43. Major modifications of TDP-43 have been identified as being hyperphosphorylation and proteolytic cleavage by caspases. In this review a summary of the major findings regarding the proteolytic modification of TDP-43 will be discussed as well as potential toxic-gain mechanisms these fragments may cause including cytoskeletal disruptions. Histol Histopathol 24, 1081-1086 (2009)

Key words: Pick’s disease, Pick bodies, Caspases, TDP-43, Hirano Bodies, Tau, Review, Alzheimer’s disease, FTLD-U, ALS, Actin

DOI: 10.14670/HH-24.1081