Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.
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.
Neumann
Manuela
M
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Sampathu
Deepak M
DM
Kwong
Linda K
LK
Truax
Adam C
AC
Micsenyi
Matthew C
MC
Chou
Thomas T
TT
Bruce
Jennifer
J
Schuck
Theresa
T
Grossman
Murray
M
Clark
Christopher M
CM
McCluskey
Leo F
LF
Miller
Bruce L
BL
Masliah
Eliezer
E
Mackenzie
Ian R
IR
Feldman
Howard
H
Feiden
Wolfgang
W
Kretzschmar
Hans A
HA
Trojanowski
John Q
JQ
Lee
Virginia M-Y
VM
D000595:Amino Acid Sequence; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology; D000911:Antibodies, Monoclonal; D001923:Brain Chemistry; D002540:Cerebral Cortex / Q000737:chemistry / Q000473:pathology; D004268:DNA-Binding Proteins / Q000032:analysis* / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D003704:Dementia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005455:Fluorescent Antibody Technique; D006624:Hippocampus / Q000737:chemistry / Q000473:pathology; D006801:Humans; D015151:Immunoblotting; D008969:Molecular Sequence Data; D009046:Motor Neurons / Q000737:chemistry / Q000473:pathology; D009474:Neurons / Q000737:chemistry / Q000473:pathology; D010446:Peptide Fragments / Q000737:chemistry; D010766:Phosphorylation; D013116:Spinal Cord / Q000737:chemistry* / Q000473:pathology; D025801:Ubiquitin / Q000032:analysis*
D000911:Antibodies, Monoclonal; D004268:DNA-Binding Proteins; D010446:Peptide Fragments; D025801:Ubiquitin