Abstract
Deleterious post-translational modifications (PTMs) to the neuronal cytoskeleton are a proposed mechanistic link between accumulation of amyloid (A) β 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: Aβ, tau, apolipoprotein (apo) E, glial fibrillary acidic protein (GFAP), β-III tubulin, and β-III tubulin. Our results confirmed direct observations of others by identifying methionine (M) sulfoxides at A 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 β-III tubulin but not its heterodimeric partner, neuron-enriched β-III tubulin, a result confirmed by selective suppression of CNBr-mediated cleavage of β-III tubulin. These findings are the first comprehensive assessment of PTMs in AD and point to oxidative modification of β-III tubulin as a potential contributor to the neuronal cytoskeletal disruption that is characteristic of AD.
Original language | English (US) |
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Pages (from-to) | 1473-1483 |
Number of pages | 11 |
Journal | FASEB Journal |
Volume | 20 |
Issue number | 9 |
DOIs | |
State | Published - Jul 2006 |
Externally published | Yes |
Keywords
- Dendrites
- Gene expression
- PTMs
- Paired helical filament
ASJC Scopus subject areas
- Biotechnology
- Biochemistry
- Molecular Biology
- Genetics