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Selectively increased oxidative modifications mapped to detergent-insoluble forms of Aß and ß-III tubulin in Alzheimer’s disease

Angela M. Boutte^*, Randall L. Woltjer, Lisa J. Zimmerman, Sheryl L. Stamer, Kathleen S. Montine, Michael V. Manno, Patrick J. Cimino, Daniel C. Liebler and Thomas J. Montine¹

^* Center for Molecular Neuroscience and

Department of Biochemistry and Mass Spectrometry Research Center, Vanderbilt University, Nashville, Tennessee, USA; and ³Department of Pathology, University of Washington, Seattle, Washington, USA

¹Correspondence: Department of Pathology, University of Washington, Harborview Medical Center, Box 359791, Seattle, WA 98104, USA. E-mail: tmontine{at}u.washington.edu

Deleterious post-translational modifications (PTMs) to the neuronal cytoskeleton are a proposed mechanistic link between accumulation of amyloid (A) ß peptides and subsequent abnormalities of tau and neurodegeneration in Alzheimer’s disease (AD). Here we tested the hypothesis that PTMs on neuronal tubulins selectively accumulate in a pathological protein fraction in AD. We used new software, P-MOD, to identify comprehensively and map PTMs using mass spectral data from soluble (normal) and detergent-insoluble (pathological) protein fractions from AD, as well as total extracts from controls, for selected proteins: Aß, tau, apolipoprotein (apo) E, glial fibrillary acidic protein (GFAP), -III tubulin, and ß-III tubulin. Our results confirmed direct observations of others by identifying methionine (M) sulfoxides at Aß position 35 and numerous sites of tau phosphorylation in detergent-insoluble protein from AD, while no PTMs were enriched on primarily astrocyte-derived apoE or GFAP in this fraction. P-MOD mapped several abundant M sulfoxides to neuron-enriched ß-III tubulin but not its heterodimeric partner, neuron-enriched -III tubulin, a result confirmed by selective suppression of CNBr-mediated cleavage of ß-III tubulin. These findings are the first comprehensive assessment of PTMs in AD and point to oxidative modification of ß-III tubulin as a potential contributor to the neuronal cytoskeletal disruption that is characteristic of AD.—Boutte, A. M., Woltjer, R. L., Zimmerman, L. J., Stamer, S. L., Montine, K. S., Manno, M. V., Cimino, P. J., Liebler, D. C., Montine, T. J. Selectively increased oxidative modifications mapped to detergent-insoluble forms of Aß and ß-III tubulin in Alzheimer’s disease.

Key Words: PTMs • gene expression • paired helical filament • dendrites