Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.
Research paper by
Manuela M Neumann, Deepak M DM Sampathu, Linda K LK Kwong, Adam C AC Truax, Matthew C MC Micsenyi, Thomas T TT Chou, Jennifer J Bruce, Theresa T Schuck, Murray M Grossman, Christopher M CM Clark, Leo F LF McCluskey, Bruce L BL Miller, Eliezer E Masliah, Ian R IR Mackenzie, Howard H Feldman, Wolfgang W Feiden, Hans A HA Kretzschmar, John Q JQ Trojanowski, Virginia M-Y VM Lee
Ubiquitin-positive, tau- and alpha-synuclein-negative inclusions are hallmarks of frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis. Although the identity of the ubiquitinated protein specific to either disorder was unknown, we showed that TDP-43 is the major disease protein in both disorders. Pathologic TDP-43 was hyper-phosphorylated, ubiquitinated, and cleaved to generate C-terminal fragments and was recovered only from affected central nervous system regions, including hippocampus, neocortex, and spinal cord. TDP-43 represents the common pathologic substrate linking these neurodegenerative disorders.