Two years ago, Penn neurodegenerative researchers determined that a well-known chemical process called acetylation has a previously unrecognized association with one of the biological processes associated with Alzheimer’s disease and related disorders. The findings were published in Nature Communications by first author postdoctoral fellow Todd Cohen, PhD, and senior author Virginia M.-Y. Lee, PhD, director of Penn’s Center for Neurodegenerative Disease Research.
Tau is one of the primary disease proteins associated with neurodegenerative diseases. Tau proteins are expressed primarily in the central nervous system where they help with the assembly and stability of microtubules, protein structures that are the backbone of nerve-cell axons.In the Nature Communications paper, acetylation was only detected in diseased brain tissue from patients with Alzheimer’s disease or fronto-temporal degeneration, suggesting it may have a role in the transformation of tau into the fibrils that lead to disease. Cohen and Lee demonstrated that tau acetylation led to a loss in microtubule assembly and an increased ability of the protein to form clumps. This, in turn, suggested that acetylation is a potential target for drug discovery and biomarker development for Alzheimer’s and related tauopathies.
Now, in an update to this line of research published recently in Nature Structural and Molecular Biology, Cohen, Lee, and the CNDR team have found an unusual behavior in tau.
Tau is literally its own worst enemy. “The big finding of this paper is that tau is actually an enzyme that adds the acetyl group to itself, a process called autoacetylation, a biological concept that could have profound implications for normal tau function in the brain as well as what happens during disease,” says Cohen.
There is a precedent for this type of self-enzymatic phenomena, but not in the neurodegenerative field. It’s known mostly from structural biology studies of basic yeast enzymes and their closest human counterparts.
For the past 25 years or so, phosphorylation of tau (the adding of phosphate chemical groups as opposed to the acetyl group in acetylation) has been the focus of tau neurodegeneration research efforts, but now…"this is what you hope happens in science,” says Cohen. “Phosphorylation may not be the whole story. Our study suggests acetylation and phosphorylation in conjunction could play an important role in driving tau pathogenesis. This makes sense, since combinations of chemical modifications could provide additional layers of regulation for especially critical proteins such as tau.”
Acetylation has a dramatic effect on tau function, so the team looked for an enzyme that fit the bill, and it turned out, one of the enzymes is tau itself.
It wasn’t a Eureka moment, says Cohen. Results of incremental experiments over the last two years pointed to tau as the enzyme, “but we thought this was nonsense, but after a while I said to Virginia, 'Tau has to be enzymatic,'” he recalls.
Although tau is not a strong enzyme – one that transfers many acetyl groups in a short period of time to the target molecule it is working on – its autoacetylation affects can add up substantially over the long haul.
Cohen characterizes this new chapter in his research as a beginning: “We might be able to therapeutically block tau’s enzymatic activity, so we would look for an acetyl transferase inhibitor for tau. We will also be looking to see if we can increase tau’s enzymatic activity so we can induce neurodegeneration in mice to tease apart exactly how autoacetylation messes up tau’s normal function.”Cohen TJ, Friedmann D, Hwang AW, Marmorstein R, & Lee VM (2013). The microtubule-associated tau protein has intrinsic acetyltransferase activity. Nature structural & molecular biology PMID: 23624859