By
Edward Quach
Paper: Cohen, T. J. et al. The acetylation of tau inhibits its function and promotes pathological
tau aggregation. Nat Com. 2, 252 (2011).
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3120096/pdf/nihms299343.pdf
Clumpy Tau: The Role of Acetylation in Brain tau Regulation and Pathologies
Expressed in the central nervous system(CNS), tau is a protein vital to cytoskeletal assembly and maintenance. In recent literature, tau has been the topic of much discussion due to its implication in many neurodegenerative diseases including Alzheimer’s and Parkinson’s. It is known that tau can be phosphorylated as a method of regulation, and that hyper-phosphorylated tau becomes insoluble and forms fibrils characteristic of many of these pathologies (or specifically, tauopathies). In addition to phosphorylation, acetylation of tau at numerous lysine residues has been observed. Unfortunately, little is known about the regulation by acetylation in tau or its role in the neurofibrillary tangles (NFTs) observed in many degenerative disorders. Thus, the authors assess tau acetylation in numerous systems in order to provide a clearer picture of
its link to disease pathogenesis.
In order to establish whether or not tau is indeed acetylated, the authors use radioactive acetyl-CoA to show binding. They also utilize an abbreviated version of the protein cut down to the microtubule (MT) binding domains. This version was shown to be tagged by radioactive acetyl groups, indicating that acetylation is possible and that acetylated lysine(s) are likely in the MT binding region. Using a spectroscopic assay, the authors showed that an acetylated version of tau were unable to form MT. This implies that acetylation may be a regulatory mechanism shutting down tau MT arranging activity. Next, in order to explore a link between the NFTs and acetylation, the authors used heparin to induce fibrilization and assayed the extent of fibrilization via the binding of ThioflavinT. The acetylated tau was quick to form fibrils, though the unacetylated tau, did not fibrilize. The authors’ argument for this linkage between acetylation and fibril formation was bolstered by the presence of separation of acetylated and unacetylated tau in the pellet and supernatant, respectively, when centrifuged. More convincing yet wasthe authors’ further linkage through electron microscopy, which showed fibrilization onlyin the acetylated tau. Using MS/MS and mutagenesis experiments, the authors identify four key lysines that are acetylated in tau. The authors use an antibody specific to an acetylated version of one of these lysines to show that characteristic fibrils in Alzheimer’s brains were composed of
acetylated tau.
Prior to this work, very little was known about tau acetylation in the CNS. The results presented shift our ways of thinking about the numerous neurodegenerative diseases characterized by these NFTs and about tau acetylation as a general cytoskeletal regulator. The relationships established by the authors will be useful in future treatment,diagnoses and overall comprehension of these complex tauopathies.
