Enhancing the TBK1-p62 axis as a therapeutic strategy for frontotemporal lobar degeneration
Frontotemporal lobar degeneration (FTLD) is the most common cause of dementia in younger people. Autophagy is a natural process where damaged proteins and mitochondria (tiny specialised structures responsible for energy production) are removed from the cell. In FTLD, autophagy is reduced, which leads to a build-up of damaged proteins (TDP-43) and damaged mitochondria in brain cells, causing them to die. Autophagy requires a protein called p62, which is activated by another protein,TBK1. In 3-4% of FTLD cases a change in the TBK1 gene leads to a mutated TBK1 protein being produced. Researchers don’t yet know how mutant TBK1 proteins cause FTLD. However, we found that two mutant TBK1 proteins did not activate p62, which reduced autophagy and caused TDP-43 to build-up in the brain. We will now test whether other mutant TBK1 proteins fail to activate p62 and cause TDP-43 and mitochondria to build-up. Our study will help researchers to understand exactly how TBK1 gene mutations cause FTLD. Increasing TBK1 levels may reduce the build-up of TDP-43 and damaged mitochondria in the brain and this could be beneficial in FTLD. Therefore, we will also test potential therapeutic compounds to find those that enhance TBK1 levels.