Neuroproteasomes Underlie Formation of Endogenous Tau/RNA Inclusions

Background To form new memories and retrieve the old ones, brain cells must be able to make new proteins. Cells carefully orchestrate this process where they replace used or faulty proteins with new ones. This balance is called proteostasis and is thought to go awry in brain diseases including Alzheimer's. Why this happens and how it relates to disease-related changes in the brain and memory loss remains unclear. Tau is a protein that is one focus of research into the causes of Alzheimer's and other neurodegenerative disorders. As part of the disease process, tau aggregates into various forms inside of cells including neurofibrillary tangles, one of the hallmarks of Alzheimer's. Studies have demonstrated that tau may co-aggregate with RNA (ribonucleic acid, a molecule that carries the genetic code from the genes in your DNA to the machinery for making proteins) as well as RNA-binding proteins, some of which are responsible for making sure the RNA is folded into the right shape to make it function correctly. Dr. Kalin Konrad-Vicario and colleagues recently discovered a new mechanism of protein turnover in the brain, which they named plasma membrane-bound neuroproteasomes (NMPs). This system degrades proteins while at the same time generating molecules that can influence the activity of other cells in the brain. However, the role of NMPs in the aggregation of tau and RNA in Alzheimer's is not well understood. Research Plan Dr. Konrad-Vicario and colleagues will study how NMP dysfunction may impact tau/RNA aggregates using nerve cells grown in laboratory dishes. The researchers will induce tau aggregations by inhibiting NMP activity. They will identify the specific forms of tau in the aggregates, as well as the types of RNAs associated with the different forms of tau. Next, the team will study whether the progression of tau aggregation can be modulated by NMP inhibition or the activity of specific RNAs. In addition, Dr. Konrad-Vicario and colleagues will further investigate the mechanisms of how NMP function regulates tau/RNA aggregations and how this may lead to Alzheimer's-related brain changes in genetically engineered Alzheimer's-like mice. Impact The findings may uncover new mechanistic insights into how the tau protein contributes to Alzheimer's progression and may also reveal potential therapeutic targets for Alzheimer's and other brain diseases.