Effects of Proteasome Inhibition on Tau Protein

• Main Author: Cheng, Shuk Yee
• Other Authors: Tandon, Anurag
• Language: en_ca
• Published: 2011
• Subjects: Tau; Proteasome
• Online Access: http://hdl.handle.net/1807/30547

The ubiquitin-proteasome system is an important proteolytic pathway implicated in the formation of neurofibrillary tangles from hyperphosphorylated tau, a pathological hallmark of tauopathies such as Alzheimer’s disease. We hypothesize that proteasome inhibition will result in tau accumulation, leading to the formation of aggregates. We established a combined pharmacological and genetic model of proteasome inhibition in SHSY-5Y neuroblastoma cells. Through lentiviral infection, we expressed a mutant T1A form of the β5 proteasome subunit to impair the chymotryptic proteolytic activity of the proteasome. Cells were then treated with different pharmacological inhibitors of the proteasome to further exacerbate the effects of mutation-mediated proteasome inhibition and tested for changes in tau expression. Contrary to our hypothesis, chronic proteasome inhibition and exposure to mild oxidative stress concurrently resulted in increased tau degradation. Therefore, although chronic proteasome inhibition was insufficient to induce changes in tau turnover, it rendered cells more vulnerable to oxidative insult.