Transmembrane protein 106B, TMEM106B, is a type II transmembrane protein located within the late endosome/lysosome of neurons and glia, plays a critical role in lysosomal function, and has implications in a variety of neurodegenerative diseases.^1,2

TMEM106B is composed of 274 amino acids comprising an N-terminal cytosolic domain, a transmembrane domain, and a C-terminal luminal domain with five glycosylation sites. The full-length protein has been shown to undergo a two-step proteolytic cleavage process, resulting in the formation of N-terminal and putative C-terminal fragments. TMEM106B regulates various aspects of lysosomal function, including morphology, movement, intracellular localization, intralysosomal pH, and the expression of several lysosomal proteins, such as cathepsin D and progranulin (PGRN). TMEM106B has also been shown to affect lysosomal trafficking in neuronal dendrites and across the axon initial segment (AIS) in motor neurons.^1,2

TMEM106B is ubiquitously expressed by many different cell types in the central nervous system (CNS), with neurons and oligodendrocytes exhibiting particularly high levels of expression. TMEM106B-deficient mice exhibit lysosomal trafficking defects in the axons of motor neurons and Purkinje cells, as well as reduced survival of Purkinje cells during aging. TMEM106B deficiency also leads to perinuclear localization of lysosomes in oligodendrocytes, resulting in trafficking defects of the main myelin membrane protein proteolipid protein (PLP) and myelination deficits.¹

TMEM106B modulates the inflammatory polarization of innate immune cells, CNS inflammation pathways, and degenerative processes. In the CNS, microglia, the resident immune cells, primarily mediate inflammation and continuously monitor the CNS environment. Dysregulated activation of microglia is known to play a crucial role in the development of neurodegenerative disorders. TMEM106B deficiency results in reduced microglial survival, proliferation, and activation in response to cuprizone (CPZ)– and lipopolysaccharide (LPS)–induced demyelination, as well as severe lysosomal defects in microglia and decreased levels of triggering receptor expressed on myeloid cells 2 (TREM2), a transmembrane protein essential for microglial proliferation and survival.¹

TMEM106B has emerged as a significant player in various neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and limbic-predominant age-related TAR DNA binding protein-43 (TDP-43) encephalopathy. A mutation in TMEM106B is responsible for hypomyelinating leukodystrophy (HLD), which encompasses a group of hereditary neurodevelopmental disorders characterized by abnormal myelination in the CNS. TMEM106B has also been identified as one of the primary contributors to brain aging. The C-terminal fragment of TMEM106B has recently been shown to form amyloid fibrils in the aged brain as well as in several neurodegenerative diseases. A TMEM106B variant was shown to provide protection in late-onset Alzheimer’s disease by helping prevent a buildup of toxic waste products within the cell, which is a consequence of lysosomal dysfunction and a common theme of neurodegenerative disorders.^1,3