The Tau Post-Translational Modification Puzzle

November 22, 2017

Can you solve it?

Microtubule associated-protein tau (tau for short) is a microtubule stabilizing protein most commonly found in neurons. Tau helps regulate transport of other proteins by binding or falling off of microtubules.

Michala Kolarova, Francisco García-Sierra, Ales Bartos, Jan Ricny, and Daniela Ripova, “Structure and Pathology of Tau Protein in Alzheimer Disease,” International Journal of Alzheimer’s Disease, vol. 2012, Article ID 731526, 13 pages, 2012. doi:10.1155/2012/731526

The binding affinity and cellular localization of tau can vary, and is regulated by many post-translational modifications (PTMs), including ubiquitination, SUMOylation, acetylation, and phosphorylation. These PTMs act like little switches on a microchip, and are attached and removed by enzymes like kinases, phosphatases, acetyltransferases, deacetylases and ubiquitin ligases that are in turn regulated by external stimuli including insulin signaling, glutamate, GABA, and neuropeptide receptors.

Mixing and matching of PTMs dynamically regulates neuronal polarization and dendritic branching. When it goes awry, the cell makes too much aggregate-prone, hyperphosphorylated species of tau, a common hallmark of Alzheimer’s disease. Hyperphosphorylated tau clumps with more tau to form tangles, which cause cell death and increase inflammation in the brain. All the different PTMs and their relative effects on tau make for an incredibly complex profile, which we have taken to calling the “PTM code”.

Crack the Code!

Someone at BioMed took the time to build a huge database of tau PTMs. Each one is mapped to the amino acid sequence of tau, and has the citation linked. Check it out to see if you can solve the tau post translational modifcation puzzle, and crack the tau code!

Tau in Alzheimer’s Disease

June 22, 2017

Tau-mediated neurodegeneration in Alzheimer’s disease

Tau acetylation causes increased tau aggregation in vitro and promotes the formation of tau tangles observed in AD brain (Cohen et al., Nat Commun, 2011).

Our Research Mission

June 22, 2017

Our Research Mission in Todd Cohen’s Lab at UNC Chapel Hill

One-liner: To identify the pathogenic mechanisms underlying neurodegenerative disease.

More specifically:

Although distinct, many of these diseases share common underlying pathogenic mechanisms. We seek to uncover the molecular pathways that promote protein aggregation and the formation of amyloid deposits that cause neurodegeneration and cognitive impairments.

Using a combination of biochemistry, genetics, and cell biology, we have identified several post-translational mechanisms including lysine acetylation, phosphorylation, and cysteine disulfide modifications that critically regulate many disease-associated proteins in the brain including the tau protein in AD and the TDP-43 protein present in ALS and FTLD patients. We have pioneered the concept that lysine acetylation, in particular, is an unanticipated, yet critical modification that promotes the evolution and maturation of pathological aggregates in a spectrum of neurodegenerative diseases.

This raises the intriguing possibility of modification-targeted therapeutics to combat normal ageing mechanisms and a broad range of neurodegenerative diseases. Ultimately, by uncovering the mechanistic details that regulate normal and aberrant protein functions in the diseased brain, can we begin to uncover the molecular platform for future drug-based therapies against these debilitating diseases.

Approach:

We utilize a multidisciplinary approach from the “bottom-up”, starting at the protein level and progressing towards more relevant models to answer fundamental questions about protein function and aggregation in neurodegenerative disease.

Relevance:

Although clinically and pathologically distinct, the disorders shown below share a common underlying pathogenic mechanism in which normally soluble proteins become abnormally sequestered into protein aggregates that can exert toxic loss and gain of functions in a tissue-specific manner.

Current research projects:

1) Tau-mediated neurodegeneration in Alzheimer’s disease