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 asignificant contribution to neurodegenerative disease research and advanced our understanding of TMEM106B protein homeostasis.