{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTMEM106B is an integral lysosomal membrane protein that plays a pivotal role in maintaining neuronal homeostasis. It regulates lysosomal enzyme levels, acidification, and proteolytic activity, thereby ensuring proper axonal transport and synaptic integrity. In various neurodegenerative disease models—including frontotemporal lobar degeneration (FTLD) associated with progranulin deficiency, tauopathies, and TDP‐43 proteinopathies—altered TMEM106B dosage (through loss or gain of function) results in impaired lysosomal protein turnover, axonal swellings, and increased pathological protein accumulation that accelerate neuronal loss and behavioral deficits."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in cellular trafficking and degradation, TMEM106B itself undergoes a regulated intramembrane proteolysis process. Lysosomal proteases first generate an N‐terminal fragment that contains the transmembrane and intracellular domains; subsequent cleavage by the GxGD aspartyl proteases SPPL2a and SPPL2b produces a rapidly degraded intracellular domain. This processing may serve to fine tune lysosomal function and downstream signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nTMEM106B also has essential roles in non‐neuronal cells of the central nervous system. In oligodendrocytes, it interacts with lysosomal proteases (for example, cathepsin D) to maintain levels of myelin proteins and sustain proper myelin lipid metabolism. In microglia, deficiency of TMEM106B leads to impaired lysosomal acidification and enzyme activity, which in turn reduces the levels of survival receptors and dampens the inflammatory as well as remyelination responses. These cell type–specific roles underscore TMEM106B’s broader importance in sustaining neural network integrity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to neurodegenerative processes, TMEM106B is implicated in non‐neuronal pathologies and adaptive responses. In metastatic lung cancer, ectopic TMEM106B expression drives the synthesis of enlarged, active lysosomal vesicles and promotes calcium‐dependent exocytosis of cathepsins in a TFEB‐dependent manner—processes that facilitate cancer cell invasion and metastasis. Furthermore, elevated TMEM106B levels in the human brain have been observed in Alzheimer’s disease and may be part of a compensatory response to tissue damage, potentially influencing APOE regulation and synaptic remodeling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Zoe A Klein, Hideyuki Takahashi, Mengxiao Ma, et al. 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