TMEM106B was originally discovered as a risk modifier in TDP-positive frontotemporal dementia, but its reach has since extended to Alzheimer’s Disease (AD), (PD), CTE, age-related cognitive decline, and functional resilience against neuropathological burden. This project will determine how TMEM106B influences lysosomal function in vivo and how this role is altered by aging and tauopathy. It interacts closely with the other projects in elucidating molecular control over lysosomal homeostats, while distinguishing itself in focusing on a genetic modifier of uncertain mechanism but remarkable influence.
The hypothesis is that TEM106B controls lysosomal homeostasis through a combination of local protein interactions and TFEB-mediated nuclear signaling. It is predicted that these interactions are governed by post-translational modifications that determine TMEM106B localization within the cell. We further propose that TMEM106B’s role in homeostasis becomes more critical with aging and disease, where mild reduction preserves lysosome function under conditions of cellular stress. To support these studies, TMEM106B knock-out and T186S knock-in mice have been created to conduct the studies in vivo, in the context of the mature brain, upon aging or in AD.
- How does TMEM106B expression affect lysosome properties in the healthy brain and does its impact change with aging or Alzheimer’s Disease?
- Does TMEM106B act via nuclear transcription, lysosomal protein stability, or both?
- What PTMs are present on TMEM106B in vivo, and does the lone coding variants alter these modifications to influence function?