Systematic Dissection of the Molecular Mechanisms Driven by Tauopathy Risk Gene KANSL1 Pathway

Pathway Grant

Le Qi, University of California Los Angeles

Alzheimer's Disease and Alzheimer’s Disease Related Dementias (AD/ADRDs) are the most common forms of dementia, affecting more than 50 million people in the world. These conditions inflict devastating effects on the patients as well as their loved ones. Sadly, there is no effective treatment for these patients. This highlights the urgent need to understand how AD/ADRDs develop and impair brain functions. A common feature of AD/ADRDs is the accumulation of toxic tangles in patients' brains. Efforts have been focused on the MAPT gene linked to these toxic tangles. A large region around the MAPT gene is inverted in about 10-20% of the people. These people have a lower risk to get many forms of dementia, including AD/ADRDs and Parkinson’s disease. However, this large region is too complex to study with traditional methods. As a result, the reason behind the protective effects of this inversion is not known. Using technology that only became available in recent years, I found that KANSL1 and LRRC37A genes were more active in brains with the inversion. I also analyzed published long-read data and found a novel gene product with KANSL1 and LRRC37A fused together (KANSL1-LRRC37A) only in people with the inversion.

I will build on these results and study the role played by KANSL1-LRRC37A on dementia. I will first assess where KANSL1-LRRC37A is located in neurons compared to the normal versions of KANSL1 and LRRC37A proteins. Next, I will study the function of this fusion protein by reducing it in neurons made from people with or without the inversion. I will look for changes in tangle accumulation and cell death in neurons. Finally, I will study how gene expression changes in neurons after reducing the levels of KANSL1-LRRC37A.

Overall, this study will help to understand why the inversion of the MAPT region affects gene expression and the risk of AD/ADRDs. The results have the potential to improve our understanding of AD/ADRDs and reveal new drug targets.