Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis by Neumann Manuela, Sampathu Deepak M, Kwong Linda K, Truax Adam C, Micsenyi Matthew C, Chou Thomas T, Bruce Jennifer, Schuck Theresa, Grossman Murray, Clark Christopher M, McCluskey Leo F, Miller Bruce L, Masliah Eliezer, Mackenzie Ian R, Feldman Howard, Feiden Wolfgang, Kretzschmar Hans A, Trojanowski John Q, Lee Virginia M-Y in Science (New York, N.Y.) (2006).

[PMID: 17023659] PubMed


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.

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