Tau nitration occurs at tyrosine 29 in the fibrillar lesions of Alzheimer's disease and other tauopathies.
The neurodegenerative tauopathies are a clinically diverse group of diseases typified by the pathological self-assembly of the microtubule-associated tau protein. Although tau nitration is believed to influence the pathogenesis of these diseases, the precise residues modified, and the resulting effects on tau function, remain enigmatic. Previously, we demonstrated that nitration at residue Tyr29 markedly inhibits the ability of tau to self-associate and stabilize the microtubule lattice (Reynolds et al., 2005b, 2006). Here, we report the first monoclonal antibody to detect nitration in a protein-specific and site-selective manner. This reagent, termed Tau-nY29, recognizes tau only when nitrated at residue Tyr29. It does not cross-react with wild-type tau, tau mutants singly nitrated at Tyr18, Tyr197, and Tyr394, or other proteins known to be nitrated in neurodegenerative diseases. By Western blot analysis, Tau-nY29 detects soluble tau and paired helical filament tau from severely affected Alzheimer's brain but fails to recognize tau from normal aged brain. This observation suggests that nitration at Tyr29 is a disease-related event that may alter the intrinsic ability of tau to self-polymerize. In Alzheimer's brain, Tau-nY29 labels the fibrillar triad of tau lesions, including neurofibrillary tangles, neuritic plaques, and, to a lesser extent, neuropil threads. Intriguingly, although Tau-nY29 stains both the neuronal and glial tau pathology of Pick disease, it detects only the neuronal pathology in corticobasal degeneration and progressive supranuclear palsy without labeling the predominant glial pathology. Collectively, our findings provide the first direct evidence that site-specific tau nitration is linked to the progression of the neurodegenerative tauopathies.
Reynolds
Matthew R
MR
Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA. m-reynolds@md.northwestern.edu
Reyes
Juan F
JF
Fu
Yifan
Y
Bigio
Eileen H
EH
Guillozet-Bongaarts
Angela L
AL
Berry
Robert W
RW
Binder
Lester I
LI
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D016874:Neurofibrillary Tangles / Q000235:genetics / Q000378:metabolism*; D009566:Nitrates / Q000378:metabolism*; D024801:Tauopathies / Q000235:genetics / Q000378:metabolism; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D009566:Nitrates; D016875:tau Proteins; D014443:Tyrosine