Poster abstracts

Poster number 3 submitted by Grace Cooper

Lysine methylation is an endogenous post-translational modification of tau protein in human brain and a modulator of aggregation propensity

Grace L. Cooper (Department of Molecular and Cellular Biochemistry, The Ohio State University College of Medicine, Columbus, Ohio, USA), Kristen E. Funk (Department of Molecular and Cellular Biochemistry, The Ohio State University College of Medicine, Columbus, Ohio, USA), Kelsey N. Schafer (Department of Molecular and Cellular Biochemistry, The Ohio State University College of Medicine, Columbus, Ohio, USA), Stefani N. Thomas, Dongping Liao, David J. Clark (Molecular and Cellular Cancer Biology Program, Greenbaum Cancer Center, University of Maryland, Baltimore, Maryland, USA), Austin J Yang (Molecular and Cellular Cancer Biology Program, Greenbaum Cancer Center, University of Maryland, Baltimore, Maryland, USA), Jeff Kuret (Department of Molecular and Cellular Biochemistry, The Ohio State University College of Medicine, Columbus, Ohio, USA)

Abstract:
Alzheimer’s Disease (AD) is the most common form of dementia, and there is currently no cure or preventative treatment. AD is defined by the appearance of two lesions believed to contribute to the pathogenesis of AD: extracellular beta-amyloid plaques and intracellular neurofibrillary tangles (NFTs) composed of tau protein. However, NFTs better correlate with disease and symtom progression, and are used to diagnose AD. Normal monomeric tau stabilizes microtubules and promotes their assembly. In AD, tau aggregates into long fibrils. Candidate triggers for this change include post translational modifications (PTMs), such as phosphorylation. PTMs of Lys residues can also modulate tau aggregation propensity. But Lys modifications have not been shown at single residue resolution in human brain specimens.
Tau was isolated from normal human brain and analyzed using mass spectrometry, revealing Lys methylation as a novel tau PTM. The modification clustered predominantly in the region of tau that mediates aggregation. Recombinant tau was methylated chemically to create samples with varying methylation stoichiometry. Studies reveal that at low, physiological levels, methylation does not inhibit tau’s ability to promote microtubule assembly, but even low levels of methylation are able to inhibit tau aggregation. Aggregation studies reveal that methylation inhibits aggregation by increasing the amount of protein needed to form aggregates by increasing tau’s dissociation rate from fibrils, and decreasing the fibril extension rate. Methylation also slows aggregation by depressing fibril nucleation, the rate limiting step in fibril formation.
Together these data show that low-occupancy methylation is a normal human tau PTM that does not affect tau’s normal function, but that depresses tau aggregation. Methylation could be a potential regulatory PTM of tau. Maintaining or increasing tau methylation could be a therapeutic approach for slowing NFT formation in AD.

Keywords: Tau protein, aggregation, post-translational modification