Dual modification of Alzheimer's disease PHF-tau protein by lysine methylation and ubiquitylation: A mass spectrometry approach

Greenebaum Cancer Center, University of Maryland, Baltimore, MD 21201, USA.
Acta Neuropathologica (Impact Factor: 10.76). 01/2012; 123(1):105-17. DOI: 10.1007/s00401-011-0893-0
Source: PubMed


In sporadic Alzheimer’s disease (AD), neurofibrillary lesion formation is preceded by extensive post-translational modification of the microtubule associated protein tau. To identify the modification signature associated with tau lesion formation at single amino acid resolution, immunopurified paired helical filaments were isolated from AD brain and subjected to nanoflow liquid chromatography–tandem mass spectrometry analysis. The resulting spectra identified monomethylation of lysine residues as a new tau modification. The methyl-lysine was distributed among seven residues located in the projection and microtubule binding repeat regions of tau protein, with one site, K254, being a substrate for a competing lysine modification, ubiquitylation. To characterize methyl lysine content in intact tissue, hippocampal sections prepared from post mortem late-stage AD cases were subjected to double-label confocal fluorescence microscopy using anti-tau and anti-methyl lysine antibodies. Anti-methyl lysine immunoreactivity colocalized with 78 ± 13% of neurofibrillary tangles in these specimens. Together these data provide the first evidence that tau in neurofibrillary lesions is post-translationally modified by lysine methylation.

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Available from: Stefani N Thomas
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    • "The highly phosphorylated ordered structures comprised of insoluble tau that are observed in human tauopathies are in stark contrast to normal tau protein that exists in a moderately phosphorylated soluble form and is predominantly found in neurons. Post-translational modifications of tau are common features in tauopathy, and include changes in serine/threonine and tyrosine phosphorylation [9] [10] [11], ubiquitination [12], acetylation [13], methylation [14], nitration [15], and truncation [16]. However, although a number of protein kinases have been suggested as candidates for tau modification in the tauopathies, the identity of the critical kinases that might trigger tau pathogenesis, remain enigmatic [17]. "
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    ABSTRACT: Tau has a well-established role as a microtubule-associated protein, in which it stabilizes the neuronal cytoskeleton. This function of tau is influenced by tau phosphorylation state, which is significantly increased in Alzheimer's disease and related tauopathies. Disruptions to the cytoskeleton in disease-affected neurons include reduced length and numbers of stable microtubules, and their diminished stability is associated with increased tau phosphorylation in disease. Tau is also localized in the nucleus and plasma membrane of neurons, where it could have roles in DNA repair and cell signaling. Most recently, potential roles for extracellular tau have been highlighted. The release of tau from neurons is a physiological process that can be regulated by neuronal activity and extracellular tau may play a role in inter-neuronal signaling. In addition, recent studies have suggested that the misfolding of tau in diseased brain leads to abnormal conformations of tau that can be taken up by neighboring neurons. Such a mechanism may be responsible for the apparent prion-like spreading of tau pathology through the brain, which occurs in parallel with clinical progression in the tauopathies. The relationship between tau localization in neurons, tau release, and tau uptake remains to be established, as does the function of extracellular tau. More research is needed to identify disease mechanisms that drive the release and propagation of pathogenic tau and to determine the impact of extracellular tau on cognitive decline in neurodegenerative disease.
    Full-text · Article · Mar 2014 · Journal of Alzheimer's disease: JAD
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    • "In addition to the influence that PTMs exert on tau function individually, it is thought that various modifications may cooperate and compete in a coordinated fashion. For example, recently two modifications have been identified that are also lysine directed: acetylation [120] [121] and methylation [117]. Because these modifications both directly compete with ubiquitin for lysine site occupancy, there is potential for acetylation and methylation to directly affect the rate of turnover of tau protein and its motility through the endocytic pathway. "
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    ABSTRACT: Alzheimer's disease is characterized pathologically by extracellular senile plaques, intracellular neurofibrillary tangles, and granulovacuolar degeneration. It has been debated whether these hallmark lesions are markers or mediators of disease progression, and numerous paradigms have been proposed to explain the appearance of each lesion individually. However, the unfaltering predictability of these lesions suggests a single pathological nidus central to disease onset and progression. One of the earliest pathologies observed in Alzheimer's disease is endocytic dysfunction. Here we review the recent literature of endocytic dysfunction with particular focus on disrupted lysosomal fusion and propose it as a unifying hypothesis for the three most-studied lesions of Alzheimer's disease.
    Full-text · Article · Aug 2012 · International Journal of Alzheimer's Disease

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