TMEM106B is an endo-lysosomal transmembrane protein known to be a risk factor for several neurological diseases, including frontal temporal lobar degeneration with TDP-43 pathology (FTLD-TDP). Frontal temporal lobar degeneration is the most common early age of onset dementia. Previous studies revealed TMEM106B loss-of-function as a cause for lysosomal biogenesis impairment, which further contributes to the molecular pathomechanisms of dysfunctional lysosome trafficking in disease. However, there is still very little known about the physiological functions of TMEM106B and its variants in the lysosome and how TMEM106B is associated with a wide range of neurodegenerative diseases at the molecular level. Inter-organelle contact sites are important hubs for organelles such as lysosomes to crosstalk with one another, but how TMEM106B regulates lysosomal contact sites has never been studied.