Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis

M Neumann, DM Sampathu, LK Kwong, AC Truax… - Science, 2006 - science.org
M Neumann, DM Sampathu, LK Kwong, AC Truax, MC Micsenyi, TT Chou, J Bruce…
Science, 2006science.org
Ubiquitin-positive, tau-and α-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 …
Ubiquitin-positive, tau- and α-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.
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