Skip to main content

Advertisement

SpringerLink
Log in

Physiological and pathological functions of TMEM106B: a gene associated with brain aging and multiple brain disorders

  • Review
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

TMEM106B, encoding a lysosome membrane protein, has been recently associated with brain aging, hypomyelinating leukodystrophy and multiple neurodegenerative diseases, such as frontotemporal lobar degeneration (FTLD) and limbic-predominant age-related TDP-43 encephalopathy (LATE). During the past decade, considerable progress has been made towards our understanding of the cellular and physiological functions of TMEM106B. TMEM106B regulates many aspects of lysosomal function, including lysosomal pH, lysosome movement, and lysosome exocytosis. Both an increase and decrease in TMEM106B levels result in lysosomal abnormalities. In mouse models, TMEM106B deficiency leads to lysosome trafficking and myelination defects and FTLD related pathology. In humans, alterations in TMEM106B levels or function are intimately linked to neuronal proportions, brain aging, and brain disorders. Further elucidation of the physiological function of TMEM106B and changes in TMEM106B under pathological conditions will facilitate therapeutic development to treat brain disorders associated with TMEM106B.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Adams HH, Verhaaren BF, Vrooman HA, Uitterlinden AG, Hofman A, van Duijn CM et al (2014) TMEM106B influences volume of left-sided temporal lobe and interhemispheric structures in the general population. Biol Psychiatry 76:503–508. https://doi.org/10.1016/j.biopsych.2014.03.006

    Article  CAS  PubMed  Google Scholar 

  2. Arrant AE, Nicholson AM, Zhou X, Rademakers R, Roberson ED (2018) Partial Tmem106b reduction does not correct abnormalities due to progranulin haploinsufficiency. Mol Neurodegener 13:32. https://doi.org/10.1186/s13024-018-0264-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C et al (2006) Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442:916–919

    Article  CAS  Google Scholar 

  4. Bateman A, Bennett HP (2009) The granulin gene family: from cancer to dementia. BioEssays 31:1245–1254. https://doi.org/10.1002/bies.200900086

    Article  CAS  PubMed  Google Scholar 

  5. Bieniek KF, Ross OA, Cormier KA, Walton RL, Soto-Ortolaza A, Johnston AE et al (2015) Chronic traumatic encephalopathy pathology in a neurodegenerative disorders brain bank. Acta Neuropathol 130:877–889. https://doi.org/10.1007/s00401-015-1502-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Bonifacino JS, Neefjes J (2017) Moving and positioning the endolysosomal system. Curr Opin Cell Biol 47:1–8. https://doi.org/10.1016/j.ceb.2017.01.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Brady OA, Zheng Y, Murphy K, Huang M, Hu F (2013) The frontotemporal lobar degeneration risk factor, TMEM106B, regulates lysosomal morphology and function. Hum Mol Genet 22:685–695. https://doi.org/10.1093/hmg/dds475

    Article  CAS  PubMed  Google Scholar 

  8. Brady OA, Zhou X, Hu F (2014) Regulated intramembrane proteolysis of the frontotemporal lobar degeneration risk factor, TMEM106B, by signal peptide peptidase-like 2a (SPPL2a). J Biol Chem 289:19670–19680. https://doi.org/10.1074/jbc.M113.515700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Cenik B, Sephton CF, Cenik BK, Herz J, Yu G (2012) Progranulin: a proteolytically processed protein at the crossroads of inflammation and neurodegeneration. J Biol Chem 287:32298–32306. https://doi.org/10.1074/jbc.R112.399170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Chen-Plotkin AS, Unger TL, Gallagher MD, Bill E, Kwong LK, Volpicelli-Daley L et al (2012) TMEM106B, the risk gene for frontotemporal dementia, is regulated by the microRNA-132/212 cluster and affects progranulin pathways. J Neurosci 32:11213–11227. https://doi.org/10.1523/JNEUROSCI.0521-12.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Cherry JD, Mez J, Crary JF, Tripodis Y, Alvarez VE, Mahar I et al (2018) Variation in TMEM106B in chronic traumatic encephalopathy. Acta Neuropathol Commun 6:115. https://doi.org/10.1186/s40478-018-0619-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Cohen TJ, Lee VM, Trojanowski JQ (2011) TDP-43 functions and pathogenic mechanisms implicated in TDP-43 proteinopathies. Trends Mol Med 17:659–667. https://doi.org/10.1016/j.molmed.2011.06.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Cook C, Zhang YJ, Xu YF, Dickson DW, Petrucelli L (2008) TDP-43 in neurodegenerative disorders. Expert Opin Biol Ther 8:969–978. https://doi.org/10.1517/14712598.8.7.969

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Cruchaga C, Graff C, Chiang HH, Wang J, Hinrichs AL, Spiegel N et al (2011) Association of TMEM106B gene polymorphism with age at onset in granulin mutation carriers and plasma granulin protein levels. Arch Neurol 68:581–586. https://doi.org/10.1001/archneurol.2010.350

    Article  PubMed  PubMed Central  Google Scholar 

  15. Cruts M, Gijselinck I, van der Zee J, Engelborghs S, Wils H, Pirici D et al (2006) Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 442:920–924

    Article  CAS  Google Scholar 

  16. de Araujo MEG, Liebscher G, Hess MW, Huber LA (2020) Lysosomal size matters. Traffic 21:60–75. https://doi.org/10.1111/tra.12714

    Article  CAS  PubMed  Google Scholar 

  17. Deming Y, Cruchaga C (2014) TMEM106B: a strong FTLD disease modifier. Acta Neuropathol 127:419–422. https://doi.org/10.1007/s00401-014-1249-3

    Article  PubMed  PubMed Central  Google Scholar 

  18. Feng T, Mai S, Roscoe JM, Sheng RR, Ullah M, Zhang J et al (2020) Loss of TMEM106B and PGRN leads to severe lysosomal abnormalities and neurodegeneration in mice. EMBO Rep. https://doi.org/10.15252/embr.202050219

    Article  PubMed  PubMed Central  Google Scholar 

  19. Feng T, Sheng RR, Sole-Domenech S, Ullah M, Zhou X, Mendoza CS et al (2020) A role of the frontotemporal lobar degeneration risk factor TMEM106B in myelination. Brain 143:2255–2271. https://doi.org/10.1093/brain/awaa154

    Article  PubMed  Google Scholar 

  20. Finch N, Carrasquillo MM, Baker M, Rutherford NJ, Coppola G, Dejesus-Hernandez M et al (2011) TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers. Neurology 76:467–474. https://doi.org/10.1212/WNL.0b013e31820a0e3b

    Article  CAS  PubMed  Google Scholar 

  21. Gallagher MD, Posavi M, Huang P, Unger TL, Berlyand Y, Gruenewald AL et al (2017) A dementia-associated risk variant near TMEM106B alters chromatin architecture and gene expression. Am J Hum Genet 101:643–663. https://doi.org/10.1016/j.ajhg.2017.09.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Gallagher MD, Suh E, Grossman M, Elman L, McCluskey L, Van Swieten JC et al (2014) TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions. Acta Neuropathol 127:407–418. https://doi.org/10.1007/s00401-013-1239-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Gamp AC, Tanaka Y, Lullmann-Rauch R, Wittke D, D’Hooge R, De Deyn PP et al (2003) LIMP-2/LGP85 deficiency causes ureteric pelvic junction obstruction, deafness and peripheral neuropathy in mice. Hum Mol Genet 12:631–646

    Article  CAS  Google Scholar 

  24. Gao J, Wang L, Huntley ML, Perry G, Wang X (2018) Pathomechanisms of TDP-43 in neurodegeneration. J Neurochem. https://doi.org/10.1111/jnc.14327

    Article  PubMed  PubMed Central  Google Scholar 

  25. Gass J, Cannon A, Mackenzie IR, Boeve B, Baker M, Adamson J et al (2006) Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. Hum Mol Genet 15:2988–3001

    Article  CAS  Google Scholar 

  26. Gotzl JK, Mori K, Damme M, Fellerer K, Tahirovic S, Kleinberger G et al (2014) Common pathobiochemical hallmarks of progranulin-associated frontotemporal lobar degeneration and neuronal ceroid lipofuscinosis. Acta Neuropathol 127:845–860. https://doi.org/10.1007/s00401-014-1262-6

    Article  CAS  PubMed  Google Scholar 

  27. Guo DZ, Xiao L, Liu YJ, Shen C, Lou HF, Lv Y et al (2018) Cathepsin D deficiency delays central nervous system myelination by inhibiting proteolipid protein trafficking from late endosome/lysosome to plasma membrane. Exp Mol Med 50:e457. https://doi.org/10.1038/emm.2017.291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Guo L, Shorter J (2017) Biology and pathobiology of TDP-43 and emergent therapeutic strategies. Cold Spring Harb Perspect Med. https://doi.org/10.1101/cshperspect.a024554

    Article  PubMed  PubMed Central  Google Scholar 

  29. Harding SR, Bocchetta M, Gordon E, Cash DM, Cardoso MJ, Druyeh R et al (2017) The TMEM106B risk allele is associated with lower cortical volumes in a clinically diagnosed frontotemporal dementia cohort. J Neurol Neurosurg Psychiatry 88:997–998. https://doi.org/10.1136/jnnp-2017-315641

    Article  PubMed  PubMed Central  Google Scholar 

  30. Hokkanen SRK, Kero M, Kaivola K, Hunter S, Keage HAD, Kiviharju A et al (2020) Putative risk alleles for LATE-NC with hippocampal sclerosis in population-representative autopsy cohorts. Brain Pathol 30:364–372. https://doi.org/10.1111/bpa.12773

    Article  CAS  PubMed  Google Scholar 

  31. Holler CJ, Taylor G, Deng Q, Kukar T (2017) Intracellular proteolysis of progranulin generates stable, lysosomal granulins that are haploinsufficient in patients with frontotemporal dementia caused by GRN mutations. eNeuro. https://doi.org/10.1523/ENEURO.0100-17.2017

    Article  PubMed  PubMed Central  Google Scholar 

  32. Hu T, Chen Y, Ou R, Wei Q, Cao B, Zhao B et al (2017) Association analysis of polymorphisms in VMAT2 and TMEM106B genes for Parkinson’s disease, amyotrophic lateral sclerosis and multiple system atrophy. J Neurol Sci 377:65–71. https://doi.org/10.1016/j.jns.2017.03.028

    Article  CAS  PubMed  Google Scholar 

  33. Ikemoto S, Hamano SI, Kikuchi K, Koichihara R, Hirata Y, Matsuura R et al (2020) A recurrent TMEM106B mutation in hypomyelinating leukodystrophy: a rapid diagnostic assay. Brain Dev 42:603–606. https://doi.org/10.1016/j.braindev.2020.06.002

    Article  PubMed  Google Scholar 

  34. Ito Y, Hartley T, Baird S, Venkateswaran S, Simons C, Wolf NI et al (2018) Lysosomal dysfunction in TMEM106B hypomyelinating leukodystrophy. Neurol Genet 4:e288. https://doi.org/10.1212/NXG.0000000000000288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Jun G, Ibrahim-Verbaas CA, Vronskaya M, Lambert JC, Chung J, Naj AC et al (2016) A novel Alzheimer disease locus located near the gene encoding tau protein. Mol Psychiatry 21:108–117. https://doi.org/10.1038/mp.2015.23

    Article  CAS  PubMed  Google Scholar 

  36. Jun MH, Han JH, Lee YK, Jang DJ, Kaang BK, Lee JA (2015) TMEM106B, a frontotemporal lobar dementia (FTLD) modifier, associates with FTD-3-linked CHMP2B, a complex of ESCRT-III. Mol Brain 8:85. https://doi.org/10.1186/s13041-015-0177-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kao AW, McKay A, Singh PP, Brunet A, Huang EJ (2017) Progranulin, lysosomal regulation and neurodegenerative disease. Nat Rev Neurosci 18:325–333. https://doi.org/10.1038/nrn.2017.36

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Klein ZA, Takahashi H, Ma M, Stagi M, Zhou M, Lam TT et al (2017) Loss of TMEM106B ameliorates lysosomal and frontotemporal dementia-related phenotypes in progranulin-deficient mice. Neuron 95(281–296):e286. https://doi.org/10.1016/j.neuron.2017.06.026

    Article  CAS  Google Scholar 

  39. Koga S, Lin WL, Walton RL, Ross OA, Dickson DW (2018) TDP-43 pathology in multiple system atrophy: colocalization of TDP-43 and alpha-synuclein in glial cytoplasmic inclusions. Neuropathol Appl Neurobiol 44:707–721. https://doi.org/10.1111/nan.12485

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kundu ST, Grzeskowiak CL, Fradette JJ, Gibson LA, Rodriguez LB, Creighton CJ et al (2018) TMEM106B drives lung cancer metastasis by inducing TFEB-dependent lysosome synthesis and secretion of cathepsins. Nat Commun 9:2731. https://doi.org/10.1038/s41467-018-05013-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Lang CM, Fellerer K, Schwenk BM, Kuhn PH, Kremmer E, Edbauer D et al (2012) Membrane orientation and subcellular localization of transmembrane protein 106B (TMEM106B), a major risk factor for frontotemporal lobar degeneration. J Biol Chem 287:19355–19365. https://doi.org/10.1074/jbc.M112.365098

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lattante S, Le Ber I, Galimberti D, Serpente M, Rivaud-Pechoux S, Camuzat A et al (2014) Defining the association of TMEM106B variants among frontotemporal lobar degeneration patients with GRN mutations and C9orf72 repeat expansions. Neurobiol Aging 35(2658):e2651-2658. https://doi.org/10.1016/j.neurobiolaging.2014.06.023

    Article  CAS  Google Scholar 

  43. Li Z, Farias FHG, Dube U, Del-Aguila JL, Mihindukulasuriya KA, Fernandez MV et al (2020) The TMEM106B FTLD-protective variant, rs1990621, is also associated with increased neuronal proportion. Acta Neuropathol 139:45–61. https://doi.org/10.1007/s00401-019-02066-0

    Article  CAS  PubMed  Google Scholar 

  44. Lie PPY, Nixon RA (2019) Lysosome trafficking and signaling in health and neurodegenerative diseases. Neurobiol Dis 122:94–105. https://doi.org/10.1016/j.nbd.2018.05.015

    Article  CAS  PubMed  Google Scholar 

  45. Ling SC, Polymenidou M, Cleveland DW (2013) Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron 79:416–438. https://doi.org/10.1016/j.neuron.2013.07.033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Lu RC, Wang H, Tan MS, Yu JT, Tan L (2014) TMEM106B and APOE polymorphisms interact to confer risk for late-onset Alzheimer’s disease in Han Chinese. J Neural Transm (Vienna) 121:283–287. https://doi.org/10.1007/s00702-013-1106-x

    Article  CAS  Google Scholar 

  47. Luningschror P, Werner G, Stroobants S, Kakuta S, Dombert B, Sinske D et al (2020) The FTLD risk factor TMEM106B regulates the transport of lysosomes at the axon initial segment of motoneurons. Cell Rep 30(3506–3519):e3506. https://doi.org/10.1016/j.celrep.2020.02.060

    Article  CAS  Google Scholar 

  48. Menzies FM, Fleming A, Caricasole A, Bento CF, Andrews SP, Ashkenazi A et al (2017) Autophagy and neurodegeneration: pathogenic mechanisms and therapeutic opportunities. Neuron 93:1015–1034. https://doi.org/10.1016/j.neuron.2017.01.022

    Article  CAS  PubMed  Google Scholar 

  49. Milind N, Preuss C, Haber A, Ananda G, Mukherjee S, John C et al (2020) Transcriptomic stratification of late-onset Alzheimer’s cases reveals novel genetic modifiers of disease pathology. PLoS Genet 16:e1008775. https://doi.org/10.1371/journal.pgen.1008775

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Neary D, Snowden J, Mann D (2005) Frontotemporal dementia. Lancet Neurol 4:771–780

    Article  Google Scholar 

  51. Nelson PT, Dickson DW, Trojanowski JQ, Jack CR, Boyle PA, Arfanakis K et al (2019) Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report. Brain 142:1503–1527. https://doi.org/10.1093/brain/awz099

    Article  PubMed  PubMed Central  Google Scholar 

  52. Nelson PT, Wang W-X, Partch AB, Monsell SE, Valladares O, Ellingson SR et al (2015) Reassessment of risk genotypes ( GRN, TMEM106B, and ABCC9 variants) associated with hippocampal sclerosis of aging pathology. J Neuropathol Exp Neurol 74:75–84. https://doi.org/10.1097/nen.0000000000000151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT et al (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133. https://doi.org/10.1126/science.1134108

    Article  CAS  PubMed  Google Scholar 

  54. Nicholson AM, Finch NA, Wojtas A, Baker MC, Perkerson RB 3rd, Castanedes-Casey M et al (2013) TMEM106B p. T185S regulates TMEM106B protein levels: implications for frontotemporal dementia. J Neurochem 126:781–791. https://doi.org/10.1111/jnc.12329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Nicholson AM, Zhou X, Perkerson RB, Parsons TM, Chew J, Brooks M et al (2018) Loss of Tmem106b is unable to ameliorate frontotemporal dementia-like phenotypes in an AAV mouse model of C9ORF72-repeat induced toxicity. Acta Neuropathol Commun 6:42. https://doi.org/10.1186/s40478-018-0545-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Paushter DH, Du H, Feng T, Hu F (2018) The lysosomal function of progranulin, a guardian against neurodegeneration. Acta Neuropathol 136:1–17. https://doi.org/10.1007/s00401-018-1861-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Pottier C, Zhou X, Perkerson RB, Baker M, Jenkins GD, Serie DJ et al (2018) Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study. Lancet Neurol 17:548–558. https://doi.org/10.1016/s1474-4422(18)30126-1

    Article  PubMed  PubMed Central  Google Scholar 

  58. Prolo LM, Vogel H, Reimer RJ (2009) The lysosomal sialic acid transporter sialin is required for normal CNS myelination. J Neurosci 29:15355–15365. https://doi.org/10.1523/JNEUROSCI.3005-09.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Pu J, Guardia CM, Keren-Kaplan T, Bonifacino JS (2016) Mechanisms and functions of lysosome positioning. J Cell Sci 129:4329–4339. https://doi.org/10.1242/jcs.196287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Ratnavalli E, Brayne C, Dawson K, Hodges JR (2002) The prevalence of frontotemporal dementia. Neurology 58:1615–1621

    Article  CAS  Google Scholar 

  61. Ren Y, van Blitterswijk M, Allen M, Carrasquillo MM, Reddy JS, Wang X et al (2018) TMEM106B haplotypes have distinct gene expression patterns in aged brain. Mol Neurodegener 13:35. https://doi.org/10.1186/s13024-018-0268-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Renton AE, Chio A, Traynor BJ (2014) State of play in amyotrophic lateral sclerosis genetics. Nat Neurosci 17:17–23. https://doi.org/10.1038/nn.3584

    Article  CAS  PubMed  Google Scholar 

  63. Rhinn H, Abeliovich A (2017) Differential aging analysis in human cerebral cortex identifies variants in TMEM106B and GRN that regulate aging phenotypes. Cell Syst 4(404–415):e405. https://doi.org/10.1016/j.cels.2017.02.009

    Article  CAS  Google Scholar 

  64. Rutherford NJ, Carrasquillo MM, Li M, Bisceglio G, Menke J, Josephs KA et al (2012) TMEM106B risk variant is implicated in the pathologic presentation of Alzheimer disease. Neurology 79:717–718. https://doi.org/10.1212/WNL.0b013e318264e3ac

    Article  PubMed  PubMed Central  Google Scholar 

  65. Saftig P, Puertollano R (2020) How lysosomes sense, integrate, and cope with stress. Trends Biochem Sci. https://doi.org/10.1016/j.tibs.2020.09.004

    Article  PubMed  Google Scholar 

  66. Schmiedt ML, Blom T, Blom T, Kopra O, Wong A, von Schantz-Fant C et al (2012) Cln5-deficiency in mice leads to microglial activation, defective myelination and changes in lipid metabolism. Neurobiol Dis 46:19–29. https://doi.org/10.1016/j.nbd.2011.12.009

    Article  CAS  PubMed  Google Scholar 

  67. Schwenk BM, Lang CM, Hogl S, Tahirovic S, Orozco D, Rentzsch K et al (2014) The FTLD risk factor TMEM106B and MAP6 control dendritic trafficking of lysosomes. EMBO J 33:450–467. https://doi.org/10.1002/embj.201385857

    Article  CAS  PubMed  Google Scholar 

  68. Scotter EL, Chen HJ, Shaw CE (2015) TDP-43 proteinopathy and ALS: insights into disease mechanisms and therapeutic targets. Neurotherapeutics 12:352–363. https://doi.org/10.1007/s13311-015-0338-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Settembre C, Di Malta C, Polito VA, Arencibia MG, Vetrini F, Erdin S et al (2011) TFEB links autophagy to lysosomal biogenesis. Science 332:1429–1433. https://doi.org/10.1126/science.1204592

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Simons C, Dyment D, Bent SJ, Crawford J, D’Hooghe M, Kohlschutter A et al (2017) A recurrent de novo mutation in TMEM106B causes hypomyelinating leukodystrophy. Brain 140:3105–3111. https://doi.org/10.1093/brain/awx314

    Article  PubMed  PubMed Central  Google Scholar 

  71. Simons M, Trajkovic K (2006) Neuron-glia communication in the control of oligodendrocyte function and myelin biogenesis. J Cell Sci 119:4381–4389. https://doi.org/10.1242/jcs.03242

    Article  CAS  PubMed  Google Scholar 

  72. Stagi M, Klein ZA, Gould TJ, Bewersdorf J, Strittmatter SM (2014) Lysosome size, motility and stress response regulated by frontotemporal dementia modifier TMEM106B. Mol Cell Neurosci 61:226–240. https://doi.org/10.1016/j.mcn.2014.07.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Stroobants S, D’Hooge R, Damme M (2020) Aged Tmem106b knockout mice display gait deficits in coincidence with Purkinje cell loss and only limited signs of non-motor dysfunction. Brain Pathol. https://doi.org/10.1111/bpa.12903

    Article  PubMed  Google Scholar 

  74. Suzuki H, Matsuoka M (2016) The lysosomal trafficking transmembrane protein 106B is linked to cell death. J Biol Chem 291:21448–21460. https://doi.org/10.1074/jbc.M116.737171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Trivedi PC, Bartlett JJ, Pulinilkunnil T (2020) Lysosomal biology and function: modern view of cellular debris bin. Cells. https://doi.org/10.3390/cells9051131

    Article  PubMed  PubMed Central  Google Scholar 

  76. Tropea TF, Mak J, Guo MH, Xie SX, Suh E, Rick J et al (2019) TMEM106B Effect on cognition in Parkinson disease and frontotemporal dementia. Ann Neurol 85:801–811. https://doi.org/10.1002/ana.25486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. van Blitterswijk M, Mullen B, Nicholson AM, Bieniek KF, Heckman MG, Baker MC et al (2014) TMEM106B protects C9ORF72 expansion carriers against frontotemporal dementia. Acta Neuropathol 127:397–406. https://doi.org/10.1007/s00401-013-1240-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Van Deerlin VM, Sleiman PM, Martinez-Lage M, Chen-Plotkin A, Wang LS, Graff-Radford NR et al (2010) Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions. Nat Genet 42:234–239. https://doi.org/10.1038/ng.536

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. van der Zee J, Van Langenhove T, Kleinberger G, Sleegers K, Engelborghs S, Vandenberghe R et al (2011) TMEM106B is associated with frontotemporal lobar degeneration in a clinically diagnosed patient cohort. Brain 134:808–815. https://doi.org/10.1093/brain/awr007

    Article  PubMed  PubMed Central  Google Scholar 

  80. Vass R, Ashbridge E, Geser F, Hu WT, Grossman M, Clay-Falcone D et al (2011) Risk genotypes at TMEM106B are associated with cognitive impairment in amyotrophic lateral sclerosis. Acta Neuropathol 121:373–380. https://doi.org/10.1007/s00401-010-0782-y

    Article  PubMed  Google Scholar 

  81. Werner G, Damme M, Schludi M, Gnörich J, Wind K, Fellerer K et al (2020) Loss of TMEM106B potentiates lysosomal and FTD-like pathology in progranulin deficient mice. EMBO Rep. https://doi.org/10.15252/embr.202050241

    Article  PubMed  PubMed Central  Google Scholar 

  82. White CC, Yang HS, Yu L, Chibnik LB, Dawe RJ, Yang J et al (2017) Identification of genes associated with dissociation of cognitive performance and neuropathological burden: multistep analysis of genetic, epigenetic, and transcriptional data. PLoS Med 14:e1002287. https://doi.org/10.1371/journal.pmed.1002287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Winterstein C, Trotter J, Kramer-Albers EM (2008) Distinct endocytic recycling of myelin proteins promotes oligodendroglial membrane remodeling. J Cell Sci 121:834–842. https://doi.org/10.1242/jcs.022731

    Article  CAS  PubMed  Google Scholar 

  84. Yan H, Kubisiak T, Ji H, Xiao J, Wang J, Burmeister M (2018) The recurrent mutation in TMEM106B also causes hypomyelinating leukodystrophy in China and is a CpG hotspot. Brain 141:e36. https://doi.org/10.1093/brain/awy029

    Article  PubMed  Google Scholar 

  85. Yang HS, White CC, Klein HU, Yu L, Gaiteri C, Ma Y et al (2020) Genetics of gene expression in the aging human brain reveal TDP-43 proteinopathy pathophysiology. Neuron 107(496–508):e496. https://doi.org/10.1016/j.neuron.2020.05.010

    Article  CAS  Google Scholar 

  86. Yu L, Chen Y, Tooze SA (2018) Autophagy pathway: cellular and molecular mechanisms. Autophagy 14:207–215. https://doi.org/10.1080/15548627.2017.1378838

    Article  CAS  PubMed  Google Scholar 

  87. Yu L, De Jager PL, Yang J, Trojanowski JQ, Bennett DA, Schneider JA (2015) The TMEM106B locus and TDP-43 pathology in older persons without FTLD. Neurology 84:927–934. https://doi.org/10.1212/WNL.0000000000001313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Zhou X, Brooks M, Jiang P, Koga S, Zuberi AR, Baker MC et al (2020) Loss of Tmem106b exacerbates FTLD pathologies and causes motor deficits in progranulin-deficient mice. EMBO Rep. https://doi.org/10.15252/embr.202050197

    Article  PubMed  PubMed Central  Google Scholar 

  89. Zhou X, Nicholson AM, Ren Y, Brooks M, Jiang P, Zuberi A et al (2020) Loss of TMEM106B leads to myelination deficits: implications for frontotemporal dementia treatment strategies. Brain 143:1905–1919. https://doi.org/10.1093/brain/awaa141

    Article  PubMed  Google Scholar 

  90. Zhou X, Sun L, Brady OA, Murphy KA, Hu F (2017) Elevated TMEM106B levels exaggerate lipofuscin accumulation and lysosomal dysfunction in aged mice with progranulin deficiency. Acta Neuropathol Commun 5:9. https://doi.org/10.1186/s40478-017-0412-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Mohammed Ullah and Isabel I. Katz for proofreading this manuscript and Dr. Alice S. Chen-Plotkin for helpful comments. This work is supported by NINDS/NIA (R01NS088448 & R01NS095954) and the Bluefield project to cure frontotemporal dementia to F.H.

Author information

Authors and Affiliations

  1. Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, 345 Weill Hall, Ithaca, NY, 14853, USA

    Tuancheng Feng, Alexander Lacrampe & Fenghua Hu

Authors
  1. Tuancheng Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alexander Lacrampe
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fenghua Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fenghua Hu.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Feng, T., Lacrampe, A. & Hu, F. Physiological and pathological functions of TMEM106B: a gene associated with brain aging and multiple brain disorders. Acta Neuropathol 141, 327–339 (2021). https://doi.org/10.1007/s00401-020-02246-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-020-02246-3

Keywords

Search

Navigation