Alzheimer's disease (AD) is a progressive amnestic disorder typified by the pathological self assembly of the microtubule-associated tau (T) protein into neurofibrillary tangles (NFTs). Important to NFT formation are numerous modifications of T including phosphorylation, truncation, and conformational changes. In addition, AD-associated inflammation promotes the formation of peroxynitrite, a potent nitrating agent that can modify protein tyrosine residues. Nitration occurs with biological specificity and can profoundly affect protein folding and function. Increased levels of nitrated proteins have been reported in AD brain and cerebrospinal fluid, and several groups have localized 3- nitrotyrosine to NFTs in AD brain. Antibodies specific to nitrated a synuclein decorate the signature protein aggregates of Parkinson's disease and other synucleinopathies. Similarly, immunological probes raised against nitrated a-synuclein also recognize nitrated T selectively stained NFTs and fibrillar T inclusions in AD and other tauopathies. This data suggests that nitration of select proteins may facilitate their misfolding and deposition in neurodegenerative disease. The goal of this proposal is to delineate the relationship between T nitration and NFT formation in AD. We hypothesize that site-specific nitration induces a change in T conformation that reduces its affinity for microtubules and promotes its pathological self-assembly. In this proposal, we will characterize the specific sites of T nitration in vitro and in situ, and determine the effects of nitration on T folding and function.
| Reynolds, Matthew R; Berry, Robert W; Binder, Lester I (2007) Nitration in neurodegeneration: deciphering the ""Hows"" ""nYs"". Biochemistry 46:7325-36 |
| Reynolds, Matthew R; Reyes, Juan F; Fu, Yifan et al. (2006) Tau nitration occurs at tyrosine 29 in the fibrillar lesions of Alzheimer's disease and other tauopathies. J Neurosci 26:10636-45 |
| Reynolds, Matthew R; Lukas, Thomas J; Berry, Robert W et al. (2006) Peroxynitrite-mediated tau modifications stabilize preformed filaments and destabilize microtubules through distinct mechanisms. Biochemistry 45:4314-26 |
| Reynolds, Matthew R; Berry, Robert W; Binder, Lester I (2005) Site-specific nitration differentially influences tau assembly in vitro. Biochemistry 44:13997-4009 |
