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9.B.23.  The TMEM106 (TMEM106) Family 

TMEM106B variants are genetically associated with frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), and are considered a major risk factor for this disease. TMEM106B may also be involved in other pathologies such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Schwenk et al. 2014 combined loss-of-function experiments, live imaging and proteomics to unveil the physiological roles played by TMEM106B and its binding partner MAP6 in lysosomal function and transport. Neuronal TMEM106B plays a central role in regulating lysosomal size, motility and responsiveness to stress (Stagi et al. 2014). Single-nucleotide polymorphisms: rs5848 (GRN), rs1990622 (TMEM106B), and rs704180 (ABCC9) are associated with hippocampal sclerosis of aging (HS-Aging), a common high-morbidity neurodegenerative condition in elderly persons (Nelson et al. 2015). The up-regulation of TMEM106B may increase the risk of FTLD by directly causing neurotoxicity and a pathological phenotype linked to FTLD-TDP (Suzuki and Matsuoka 2016). Nicholson and Rademakers 2016 summarized what was known about TMEM106B in 2016, including its role as a potential regulator of lysosomal function.

TMEM106C is overexpressed in hepatocellular carcinoma (HCC) cells, and inhibition of TMEM106C  suppressed the proliferation and metastasis of HCC (Duan et al. 2021). Upregulation of TMEM106C correlated with sex, tumor stage, tumor grade and prognosis. Overexpression of TMEM106C was linked to functional networks involving organelle fission and cell cycle signaling pathways through the regulation of CDK kinases, E2F1 transcription factors and miRNAs. Thus, TMEM106C contributes to malignant characteristics and poor prognosis in HCC (Duan et al. 2021).

TMEM106A is silenced by promoter region hypermethylation and suppresses gastric cancer growth by inducing apoptosis (Xu et al. 2014). It activates mouse peritoneal macrophages via the MAPK and NF-κB signaling pathways (Dai et al. 2015). It is a tumor suppressor in human renal cancer, and may play a role in prostate, breast and ovarian cancers (Wu et al. 2017; Babalyan et al. 2016; Du et al. 2018). It  inhibits cell proliferation and migration and induces apoptosis of lung cancer cells (Liu and Zhu 2018; Rizza et al. 2019). Moreover, inactivation of TMEM106A promotes lipopolysaccharide-induced inflammation via the MAPK and NF-kappaB signaling pathways in macrophages (Zhang et al. 2021). 

Since the initial identification of TMEM106B as a risk factor for frontotemporal lobar degeneration (FTLD), multiple genetic studies have found TMEM106B variants to modulate disease risk in a variety of brain disorders and healthy aging (Perneel and Rademakers 2022). Neurodegenerative disorders are typically characterized by inclusions of misfolded proteins, and since lysosomes are an important site for cellular debris clearance, lysosomal dysfunction has been linked to neurodegeneration. Consequently, many causal mutations or genetic risk variants implicated in neurodegenerative diseases encode proteins involved in endosomal-lysosomal function. As an integral lysosomal transmembrane protein, TMEM106B regulates several aspects of lysosomal function, and multiple studies have shown that proper TMEM106B protein levels are crucial for maintaining lysosomal health. Perneel and Rademakers 2022 reviewed TMEM106B research. When TMEM106B is compromised, protein and lipid clearance by the lysosome is delayed. As TMEM106B contains putative lipid- and LC3-binding sites, this may be its primary function (Shafit-Zagardo et al. 2023).





References associated with 9.B.23 family:

Babalyan, K.A., R. Sultanov, E.V. Generozov, N.B. Zakharzhevskaya, E.I. Sharova, M.N. Peshkov, A.O. Vasilev, A.V. Govorov, D.Y. Pushkar, E.A. Prilepskaya, S.A. Danilenko, E.A. Babikova, A.K. Larin, and V.M. Govorun. (2016). [Genome-wide analysis of DNA methylation in prostate cancer using the technology of Infinium HumanMethylation450 BeadChip (HM450)]. Vopr Onkol 62: 122-132. 30444590
Bauer, C.S., C.P. Webster, A.C. Shaw, J.R. Kok, L.M. Castelli, Y.H. Lin, E.F. Smith, F. Illanes-Álvarez, A. Higginbottom, P.J. Shaw, M. Azzouz, L. Ferraiuolo, G.M. Hautbergue, A.J. Grierson, and K.J. De Vos. (2022). Loss of TMEM106B exacerbates C9ALS/FTD DPR pathology by disrupting autophagosome maturation. Front Cell Neurosci 16: 1061559. 36619668
Busch, J.I., T.L. Unger, N. Jain, R. Tyler Skrinak, R.A. Charan, and A.S. Chen-Plotkin. (2016). Increased expression of the frontotemporal dementia risk factor TMEM106B causes C9orf72-dependent alterations in lysosomes. Hum Mol Genet 25: 2681-2697. 27126638
Dai, H., D. Xu, J. Su, J. Jang, and Y. Chen. (2015). Transmembrane protein 106a activates mouse peritoneal macrophages via the MAPK and NF-κB signaling pathways. Sci Rep 5: 12461. 26215746
Du, C., D. Mark, B. Wappenschmidt, B. Böckmann, B. Pabst, S. Chan, H. Cao, S. Morlot, C. Scholz, B. Auber, K. Rhiem, R. Schmutzler, T. Illig, B. Schlegelberger, and D. Steinemann. (2018). A tandem duplication of BRCA1 exons 1-19 through DHX8 exon 2 in four families with hereditary breast and ovarian cancer syndrome. Breast Cancer Res Treat 172: 561-569. 30191368
Duan, J., Y. Qian, X. Fu, M. Chen, K. Liu, H. Liu, J. Yang, C. Liu, and Y. Chang. (2021). TMEM106C contributes to the malignant characteristics and poor prognosis of hepatocellular carcinoma. Aging (Albany NY) 13:. [Epub: Ahead of Print] 33591950
Liu, J. and H. Zhu. (2018). TMEM106A inhibits cell proliferation, migration, and induces apoptosis of lung cancer cells. J. Cell. Biochem. [Epub: Ahead of Print] 30456879
Lok, H.C. and J.B. Kwok. (2021). The Role of White Matter Dysfunction and Leukoencephalopathy/Leukodystrophy Genes in the Aetiology of Frontotemporal Dementias: Implications for Novel Approaches to Therapeutics. Int J Mol Sci 22:. 33802612
Marks, J.D., V.E. Ayuso, Y. Carlomagno, M. Yue, T.W. Todd, Y. Hao, Z. Li, Z.T. McEachin, A. Shantaraman, D.M. Duong, L.M. Daughrity, K. Jansen-West, W. Shao, A. Calliari, J.G. Bejarano, M. DeTure, B. Rawlinson, M.C. Casey, M.T. Lilley, M.H. Donahue, V.M. Jawahar, B.F. Boeve, R.C. Petersen, D.S. Knopman, B. Oskarsson, N.R. Graff-Radford, Z.K. Wszolek, D.W. Dickson, K.A. Josephs, Y.A. Qi, N.T. Seyfried, M.E. Ward, Y.J. Zhang, M. Prudencio, L. Petrucelli, and C.N. Cook. (2024). TMEM106B core deposition associates with TDP-43 pathology and is increased in risk SNP carriers for frontotemporal dementia. Sci Transl Med 16: eadf9735. 38232138
Nelson, P.T., W.X. Wang, A.B. Partch, S.E. Monsell, O. Valladares, S.R. Ellingson, B.R. Wilfred, A.C. Naj, L.S. Wang, W.A. Kukull, and D.W. Fardo. (2015). Reassessment of risk genotypes (GRN, TMEM106B, and ABCC9 variants) associated with hippocampal sclerosis of aging pathology. J Neuropathol Exp Neurol 74: 75-84. 25470345
Nicholson, A.M. and R. Rademakers. (2016). What we know about TMEM106B in neurodegeneration. Acta Neuropathol 132: 639-651. 27543298
Perneel, J. and R. Rademakers. (2022). Identification of TMEM106B amyloid fibrils provides an updated view of TMEM106B biology in health and disease. Acta Neuropathol 144: 807-819. 36056242
Rizza, R., K. Hackmann, I. Paris, A. Minucci, R. De Leo, E. Schrock, A. Urbani, E. Capoluongo, G. Gelli, and P. Concolino. (2019). Novel BRCA1 Large Genomic Rearrangements in Italian Breast/Ovarian Cancer Patients. Mol Diagn Ther 23: 121-126. 30506513
Schwenk, B.M., C.M. Lang, S. Hogl, S. Tahirovic, D. Orozco, K. Rentzsch, S.F. Lichtenthaler, C.C. Hoogenraad, A. Capell, C. Haass, and D. Edbauer. (2014). The FTLD risk factor TMEM106B and MAP6 control dendritic trafficking of lysosomes. EMBO. J. 33: 450-467. 24357581
Shafit-Zagardo, B., S. Sidoli, J.E. Goldman, J.C. DuBois, J.R. Corboy, S.M. Strittmatter, H. Guzik, U. Edema, A.G. Arackal, Y.M. Botbol, E. Merheb, R.M. Nagra, and S. Graff. (2023). TMEM106B Puncta Is Increased in Multiple Sclerosis Plaques, and Reduced Protein in Mice Results in Delayed Lipid Clearance Following CNS Injury. Cells 12:. 37443768
Stagi, M., Z.A. Klein, T.J. Gould, J. Bewersdorf, and S.M. Strittmatter. (2014). Lysosome size, motility and stress response regulated by fronto-temporal dementia modifier TMEM106B. Mol. Cell Neurosci 61: 226-240. 25066864
Suzuki, H. and M. Matsuoka. (2016). The Lysosomal Trafficking Transmembrane Protein 106B Is Linked to Cell Death. J. Biol. Chem. 291: 21448-21460. 27563066
Wu, C., J. Xu, H. Wang, J. Zhang, J. Zhong, X. Zou, Y. Chen, G. Yang, Y. Zhong, D. Lai, X. Li, and A. Tang. (2017). TMEM106a is a Novel Tumor Suppressor in Human Renal Cancer. Kidney Blood Press Res 42: 853-864. 29131025
Xu, D., L. Qu, J. Hu, G. Li, P. Lv, D. Ma, M. Guo, and Y. Chen. (2014). Transmembrane protein 106A is silenced by promoter region hypermethylation and suppresses gastric cancer growth by inducing apoptosis. J Cell Mol Med 18: 1655-1666. 24975047
Zhang, X., T. Feng, X. Zhou, P.M. Sullivan, F. Hu, Y. Lou, J. Yu, J. Feng, H. Liu, and Y. Chen. (2021). Inactivation of TMEM106A promotes lipopolysaccharide-induced inflammation via the MAPK and NF-κB signaling pathways in macrophages. Clin Exp Immunol 203: 125-136. 33006758