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9.B.23.  The TMEM106B (TMEM106B) Family TMEM106B

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 and its role as a potential regulator of lysosomal function.

References associated with 9.B.23 family:

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
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
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
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