Cytoplasmic inclusions of TDP-43 in neurodegenerative diseases: a potential role for caspases.
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.
Rohn
Troy T
TT
Department of Biology, Science/Nursing Building, Room 228, Boise State University, Boise, Idaho 83725, USA. trohn@boisestate.edu
D020169:Caspases / Q000378:metabolism*; D003599:Cytoskeleton / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism*; D008954:Models, Biological; D019636:Neurodegenerative Diseases / Q000378:metabolism*
D004268:DNA-Binding Proteins; D020169:Caspases