Investigating the Regulation of TMEM106B Protein Homeostasis: Implications for Neurodegeneration.

Field of Biochemistry, Molecular and Cell Biology Ph.D. Thesis Defense Seminar – Alexander Lacrampe, Hu Lab. Friday, December 19, 2025, 9:30 AM, G01 Biotechnology Building.

Over the past decade, TMEM106B has been identified as a key player in brain disorders.

Elevated expression of TMEM106B has been associated with disease risk/severity for almost

every major neurodegenerative disease. Additionally, recent research has found that

TMEM106B also forms amyloid fibrils during brain aging and in neurodegenerative diseases.

A better understanding of how TMEM106B levels and processing are regulated has become an

urgent question in the fields of neurodegeneration and brain aging. Using biochemical

approaches, I elucidated that TMEM106B is a myristoylated protein. Myristoylation regulates

TMEM106B stability and the levels of its soluble C-terminal fragment. Furthermore,

TMEM106B myristoylation and lysosome protease cathepsin L regulate TMEM106B C-

terminal trimming. Myristoylation likely influences TMEM106B processing and levels by

regulating TMEM106B trafficking to the lysosome. Additionally, I explored the effects of the

loss-of-function mutation in TMEM106B, D252N, on TMEM106B homeostasis. The D252N

mutation reduces TMEM106B levels and increases TMEM106B CTF levels and TMEM106B

trimming. These changes in TMEM106B protein homeostasis can be rescued using a trimming-

resistant C-terminal GFP tag. These findings suggest that perturbed TMEM106B homeostasis

may contribute to disease in patients carrying the D252N mutation. Overall, my work has made

a significant contribution to neurodegenerative disease research and advanced our

understanding of TMEM106B protein homeostasis.

Zoom Meeting Link:

https://cornell.zoom.us/j/94167037137?pwd=VC8yooSyPku5gOnQNEY1mbtzXJHn97.1

Meeting ID: 941 6703 7137

Passcode: 560411