CoChat
Sign Up
Cited by 94Amyotrophic Lateral Sclerosis ResearchAlzheimer's disease research and treatmentsLysosomal Storage Disorders Research

Loss of TMEM106B and PGRN leads to severe lysosomal abnormalities and neurodegeneration in mice

Open access
Feng, Tuancheng, Mai, Shuyi, Roscoe, Jenn Marie, Sheng, Rory R, Ullah, Mohammed, Zhang, Junke, Katz, Isabel Iscol, Yu, Haiyuan +2 more·2020·The EMBO Reports
DOI 10.15252/embr.202050219PMC PMC7534636
Open this paper in CoChat — free account

Abstract

Haploinsufficiency of progranulin (PGRN) is a leading cause of frontotemporal lobar degeneration (FTLD). Loss of PGRN leads to lysosome dysfunction during aging. TMEM106B , a gene encoding a lysosomal membrane protein, is the main risk factor for FTLD with PGRN haploinsufficiency. But how TMEM106B affects FTLD disease progression remains to be determined. Here, we report that TMEM106B deficiency in mice leads to accumulation of lysosome vacuoles at the distal end of the axon initial segment in motor neurons and the development of FTLD‐related pathology during aging. Ablation of both PGRN and TMEM106B in mice results in severe neuronal loss and glial activation in the spinal cord, retina, and brain. Enlarged lysosomes are frequently found in both microglia and astrocytes. Loss of both PGRN and TMEM106B results in an increased accumulation of lysosomal vacuoles in the axon initial segment of motor neurons and enhances the manifestation of FTLD phenotypes with a much earlier onset. These results provide novel insights into the role of TMEM106B in the lysosome, in brain aging, and in FTLD pathogenesis.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.15252/embr.202050219

Cites

11 of 11 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 90

  1. Ahmed Z, Sheng H, Xu YF, Lin WL, Innes AE, Gass J, Yu X, Wuertzer CA, Hou H, Chiba S et al (2010) Accelerated lipofuscinosis and ubiquitination in granulin knockout mice suggest a role for progranulin in successful aging. Am J Pathol 177: 311– 324 20522652 PMC2893674
  2. Almeida MR, Macario MC, Ramos L, Baldeiras I, Ribeiro MH, Santana I (2016) Portuguese family with the co‐occurrence of frontotemporal lobar degeneration and neuronal ceroid lipofuscinosis phenotypes due to progranulin gene mutation. Neurobiol Aging 41: 200.e201– 200.e205 27021778
  3. Anders S, Pyl PT, Huber W (2015) HTSeq–a Python framework to work with high‐throughput sequencing data. Bioinformatics 31: 166– 169 25260700 PMC4287950
  4. 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 29929528 PMC6013889
  5. Arrant AE, Roth JR, Boyle NR, Kashyap SN, Hoffmann MQ, Murchison CF, Ramos EM, Nana AL, Spina S, Grinberg LT et al (2019) Impaired beta‐glucocerebrosidase activity and processing in frontotemporal dementia due to progranulin mutations. Acta Neuropathol Commun 7: 218 31870439 PMC6929503
  6. Bajaj L, Lotfi P, Pal R, Ronza AD, Sharma J, Sardiello M (2019) Lysosome biogenesis in health and disease. J Neurochem 148: 573– 589 30092616 PMC6368902
  7. Bateman A, Bennett HP (2009) The granulin gene family: from cancer to dementia. BioEssays 31: 1245– 1254 19795409
  8. Beel S, Moisse M, Damme M, De Muynck L, Robberecht W, Van Den Bosch L, Saftig P, Van Damme P (2017) Progranulin functions as a cathepsin D chaperone to stimulate axonal outgrowth in vivo. Hum Mol Genet 26: 2850– 2863 28453791 PMC5886064
  9. Belcastro V, Siciliano V, Gregoretti F, Mithbaokar P, Dharmalingam G, Berlingieri S, Iorio F, Oliva G, Polishchuck R, Brunetti‐Pierri N et al (2011) Transcriptional gene network inference from a massive dataset elucidates transcriptome organization and gene function. Nucleic Acids Res 39: 8677– 8688 21785136 PMC3203605
  10. van Blitterswijk M, Mullen B, Nicholson AM, Bieniek KF, Heckman MG, Baker MC, DeJesus‐Hernandez M, Finch NA, Brown PH, Murray ME et al (2014) TMEM106B protects C9ORF72 expansion carriers against frontotemporal dementia. Acta Neuropathol 127: 397– 406 24385136 PMC3944829
  11. 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 23136129 PMC3554197
  12. Brady OA, Martina JA, Puertollano R (2018) Emerging roles for TFEB in the immune response and inflammation. Autophagy 14: 181– 189 28738171 PMC5902167
  13. Butler VJ, Cortopassi WA, Argouarch AR, Ivry SL, Craik CS, Jacobson MP, Kao AW (2019) Progranulin stimulates the in vitro maturation of Pro‐cathepsin D at acidic pH. J Mol Biol 431: 1038– 1047 30690031 PMC6613950
  14. Cenik B, Sephton CF, Kutluk Cenik B, Herz J, Yu G (2012) Progranulin: a proteolytically processed protein at the crossroads of inflammation and neurodegeneration. J Biol Chem 287: 32298– 32306 22859297 PMC3463300
  15. Chang MC, Srinivasan K, Friedman BA, Suto E, Modrusan Z, Lee WP, Kaminker JS, Hansen DV, Sheng M (2017) Progranulin deficiency causes impairment of autophagy and TDP‐43 accumulation. J Exp Med 214: 2611– 2628 28778989 PMC5584112
  16. Chen‐Plotkin AS, Unger TL, Gallagher MD, Bill E, Kwong LK, Volpicelli‐Daley L, Busch JI, Akle S, Grossman M, Van Deerlin V 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 22895706 PMC3446826
  17. Clark KC, Josephson A, Benusa SD, Hartley RK, Baer M, Thummala S, Joslyn M, Sword BA, Elford H, Oh U et al (2016) Compromised axon initial segment integrity in EAE is preceded by microglial reactivity and contact. Glia 64: 1190– 1209 27100937
  18. Cong L, Ran FA, Cox D, Lin S, Barretto R, Habib N, Hsu PD, Wu X, Jiang W, Marraffini LA et al (2013) Multiplex genome engineering using CRISPR/Cas systems. Science 339: 819– 823 23287718 PMC3795411
  19. Cruchaga C, Graff C, Chiang HH, Wang J, Hinrichs AL, Spiegel N, Bertelsen S, Mayo K, Norton JB, Morris JC 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 21220649 PMC3090529
  20. Cruts M, Gijselinck I, van der Zee J, Engelborghs S, Wils H, Pirici D, Rademakers R, Vandenberghe R, Dermaut B, Martin JJ et al (2006) Null mutations in progranulin cause ubiquitin‐positive frontotemporal dementia linked to chromosome 17q21. Nature 442: 920– 924 16862115
  21. Deming Y, Cruchaga C (2014) TMEM106B: a strong FTLD disease modifier. Acta Neuropathol 127: 419– 422 24488309 PMC5494845
  22. Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, Batut P, Chaisson M, Gingeras TR (2013) STAR: ultrafast universal RNA‐seq aligner. Bioinformatics 29: 15– 21 23104886 PMC3530905
  23. Feng T, Sheng RR, Sole‐Domenech S, Ullah M, Zhou X, Mendoza CS, Enriquez LCM, Katz II, Paushter DH, Sullivan PM et al (2020) A role of the frontotemporal lobar degeneration risk factor TMEM106B in myelination. Brain 143: 2255– 2271 32572497 PMC7363491
  24. Finch N, Carrasquillo MM, Baker M, Rutherford NJ, Coppola G, Dejesus‐Hernandez M, Crook R, Hunter T, Ghidoni R, Benussi L et al (2011) TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers. Neurology 76: 467– 474 21178100 PMC3034409
  25. Gallagher MD, Suh E, Grossman M, Elman L, McCluskey L, Van Swieten JC, Al‐Sarraj S, Neumann M, Gelpi E, Ghetti B et al (2014) TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions. Acta Neuropathol 127: 407– 418 24442578 PMC4003885
  26. Gass J, Cannon A, Mackenzie IR, Boeve B, Baker M, Adamson J, Crook R, Melquist S, Kuntz K, Petersen R et al (2006) Mutations in progranulin are a major cause of ubiquitin‐positive frontotemporal lobar degeneration. Hum Mol Genet 15: 2988– 3001 16950801
  27. Gotzl JK, Mori K, Damme M, Fellerer K, Tahirovic S, Kleinberger G, Janssens J, van der Zee J, Lang CM, Kremmer E et al (2014) Common pathobiochemical hallmarks of progranulin‐associated frontotemporal lobar degeneration and neuronal ceroid lipofuscinosis. Acta Neuropathol 127: 845– 860 24619111
  28. Gotzl JK, Colombo AV, Fellerer K, Reifschneider A, Werner G, Tahirovic S, Haass C, Capell A (2018) Early lysosomal maturation deficits in microglia triggers enhanced lysosomal activity in other brain cells of progranulin knockout mice. Mol Neurodegener 13: 48 30180904 PMC6123925
  29. Gotzl JK, Brendel M, Werner G, Parhizkar S, Sebastian Monasor L, Kleinberger G, Colombo AV, Deussing M, Wagner M, Winkelmann J et al (2019) Opposite microglial activation stages upon loss of PGRN or TREM2 result in reduced cerebral glucose metabolism. EMBO Mol Med 11: e9711 31122931 PMC6554672
  30. Hafler BP, Klein ZA, Jimmy Zhou Z, Strittmatter SM (2014) Progressive retinal degeneration and accumulation of autofluorescent lipopigments in Progranulin deficient mice. Brain Res 1588: 168– 174 25234724 PMC4254024
  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 4: ENEURO.0100‐17.2017 PMC5562298 28828399
  32. Hu F, Padukkavidana T, Vaegter CB, Brady OA, Zheng Y, Mackenzie IR, Feldman HH, Nykjaer A, Strittmatter SM (2010) Sortilin‐mediated endocytosis determines levels of the frontotemporal dementia protein, progranulin. Neuron 68: 654– 667 21092856 PMC2990962
  33. da Huang W, Sherman BT, Lempicki RA (2009a) Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res 37: 1– 13 19033363 PMC2615629
  34. da Huang W, Sherman BT, Lempicki RA (2009b) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4: 44– 57 19131956
  35. Jain N, Chen‐Plotkin AS (2018) Genetic modifiers in neurodegeneration. Curr Genet Med Rep 6: 11– 19 29977663 PMC6028053
  36. Kamalainen A, Viswanathan J, Natunen T, Helisalmi S, Kauppinen T, Pikkarainen M, Pursiheimo JP, Alafuzoff I, Kivipelto M, Haapasalo A et al (2013) GRN variant rs5848 reduces plasma and brain levels of granulin in Alzheimer's disease patients. J Alzheimers Dis 33: 23– 27 22890097
  37. Kao AW, McKay A, Singh PP, Brunet A, Huang EJ (2017) Progranulin, lysosomal regulation and neurodegenerative disease. Nat Rev Neurosci 18: 325– 333 28435163 PMC6040832
  38. Klein ZA, Takahashi H, Ma M, Stagi M, Zhou M, Lam TT, Strittmatter SM (2017) Loss of TMEM106B ameliorates lysosomal and frontotemporal dementia‐related phenotypes in progranulin‐deficient mice. Neuron 95: 281– 296.e286 28728022 PMC5558861
  39. Kundu ST, Grzeskowiak CL, Fradette JJ, Gibson LA, Rodriguez LB, Creighton CJ, Scott KL, Gibbons DL (2018) TMEM106B drives lung cancer metastasis by inducing TFEB‐dependent lysosome synthesis and secretion of cathepsins. Nat Commun 9: 2731 30013069 PMC6048095
  40. Lalonde R, Strazielle C (2011) Brain regions and genes affecting limb‐clasping responses. Brain Res Rev 67: 252– 259 21356243
  41. Lang CM, Fellerer K, Schwenk BM, Kuhn PH, Kremmer E, Edbauer D, Capell A, Haass C (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 22511793 PMC3365973
  42. Lattante S, Le Ber I, Galimberti D, Serpente M, Rivaud‐Pechoux S, Camuzat A, Clot F, Fenoglio C, French research network on FTD and FTD‐ALS, Scarpini E 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.e2655 25085782
  43. Law CW, Chen Y, Shi W, Smyth GK (2014) voom: precision weights unlock linear model analysis tools for RNA‐seq read counts. Genome Biol 15: R29 24485249 PMC4053721
  44. Lee MJ, Chen TF, Cheng TW, Chiu MJ (2011) rs5848 variant of progranulin gene is a risk of Alzheimer's disease in the taiwanese population. Neurodegener Dis 8: 216– 220 21212639
  45. Lee CW, Stankowski JN, Chew J, Cook CN, Lam YW, Almeida S, Carlomagno Y, Lau KF, Prudencio M, Gao FB et al (2017) The lysosomal protein cathepsin L is a progranulin protease. Mol Neurodegener 12: 55 28743268 PMC5526245
  46. Lieu CA, Chinta SJ, Rane A, Andersen JK (2013) Age‐related behavioral phenotype of an astrocytic monoamine oxidase‐B transgenic mouse model of Parkinson's disease. PLoS ONE 8: e54200 23326597 PMC3542194
  47. Luningschror P, Werner G, Stroobants S, Kakuta S, Dombert B, Sinske D, Wanner R, Lullmann‐Rauch R, Wefers B, Wurst W 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 32160553
  48. Mali P, Yang L, Esvelt KM, Aach J, Guell M, DiCarlo JE, Norville JE, Church GM (2013) RNA‐guided human genome engineering via Cas9. Science 339: 823– 826 23287722 PMC3712628
  49. Martens LH, Zhang J, Barmada SJ, Zhou P, Kamiya S, Sun B, Min SW, Gan L, Finkbeiner S, Huang EJ et al (2012) Progranulin deficiency promotes neuroinflammation and neuron loss following toxin‐induced injury. J Clin Invest 122: 3955– 3959 23041626 PMC3484443
  50. Nabar NR, Kehrl JH (2017) The transcription factor EB links cellular stress to the immune response. Yale J Biol Med 90: 301– 315 28656016 PMC5482306
  51. Napolitano G, Ballabio A (2016) TFEB at a glance. J Cell Sci 129: 2475– 2481 27252382 PMC4958300
  52. Nelson PT, Dickson DW, Trojanowski JQ, Jack CR, Boyle PA, Arfanakis K, Rademakers R, Alafuzoff I, Attems J, Brayne C et al (2019) Limbic‐predominant age‐related TDP‐43 encephalopathy (LATE): consensus working group report. Brain 142: 1503– 1527 31039256 PMC6536849
  53. Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM et al (2006) Ubiquitinated TDP‐43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314: 130– 133 17023659
  54. Nguyen AD, Nguyen TA, Singh RK, Eberle D, Zhang J, Abate JP, Robles A, Koliwad S, Huang EJ, Maxfield FR et al (2018) Progranulin in the hematopoietic compartment protects mice from atherosclerosis. Atherosclerosis 277: 145– 154 30212683 PMC6432779
  55. Peng W, Minakaki G, Nguyen M, Krainc D (2019) Preserving lysosomal function in the aging brain: insights from neurodegeneration. Neurotherapeutics 16: 611– 634 31183763 PMC6694346
  56. Perry DC, Lehmann M, Yokoyama JS, Karydas A, Lee JJ, Coppola G, Grinberg LT, Geschwind D, Seeley WW, Miller BL et al (2013) Progranulin mutations as risk factors for Alzheimer disease. JAMA Neurol 70: 774– 778 23609919 PMC3743672
  57. 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 28330615
  58. Robinson MD, McCarthy DJ, Smyth GK (2010) edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26: 139– 140 19910308 PMC2796818
  59. Rutherford NJ, Carrasquillo MM, Li M, Bisceglio G, Menke J, Josephs KA, Parisi JE, Petersen RC, Graff‐Radford NR, Younkin SG et al (2012) TMEM106B risk variant is implicated in the pathologic presentation of Alzheimer disease. Neurology 79: 717– 718 22855871 PMC3467659
  60. Sardiello M, Palmieri M, di Ronza A, Medina DL, Valenza M, Gennarino VA, Di Malta C, Donaudy F, Embrione V, Polishchuk RS et al (2009) A gene network regulating lysosomal biogenesis and function. Science 325: 473– 477 19556463
  61. Schwenk BM, Lang CM, Hogl S, Tahirovic S, Orozco D, Rentzsch K, Lichtenthaler SF, Hoogenraad CC, Capell A, Haass C et al (2014) The FTLD risk factor TMEM106B and MAP6 control dendritic trafficking of lysosomes. EMBO J 33: 450– 467 24357581 PMC3989627
  62. Sheng J, Su L, Xu Z, Chen G (2014) Progranulin polymorphism rs5848 is associated with increased risk of Alzheimer's disease. Gene 542: 141– 145 24680777
  63. Simons C, Dyment D, Bent SJ, Crawford J, D'Hooghe M, Kohlschutter A, Venkateswaran S, Helman G, Poll‐The BT, Makowski CC et al (2017) A recurrent de novo mutation in TMEM106B causes hypomyelinating leukodystrophy. Brain 140: 3105– 3111 29186371 PMC5841038
  64. Smith KR, Damiano J, Franceschetti S, Carpenter S, Canafoglia L, Morbin M, Rossi G, Pareyson D, Mole SE, Staropoli JF et al (2012) Strikingly different clinicopathological phenotypes determined by progranulin‐mutation dosage. Am J Hum Genet 90: 1102– 1107 22608501 PMC3370276
  65. Takahashi H, Klein ZA, Bhagat SM, Kaufman AC, Kostylev MA, Ikezu T, Strittmatter SM; Alzheimer's Disease Neuroimaging Initiative (2017) Opposing effects of progranulin deficiency on amyloid and tau pathologies via microglial TYROBP network. Acta Neuropathol 133: 785– 807 28070672 PMC5391267
  66. Tanaka Y, Chambers JK, Matsuwaki T, Yamanouchi K, Nishihara M (2014) Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin‐deficient mice. Acta Neuropathol Commun 2: 78 25022663 PMC4149276
  67. Tsuruma K, Yamauchi M, Sugitani S, Otsuka T, Ohno Y, Nagahara Y, Ikegame Y, Shimazawa M, Yoshimura S, Iwama T et al (2014) Progranulin, a major secreted protein of mouse adipose‐derived stem cells, inhibits light‐induced retinal degeneration. Stem Cells Transl Med 3: 42– 53 24233842 PMC3902284
  68. Valdez C, Wong YC, Schwake M, Bu G, Wszolek ZK, Krainc D (2017) Progranulin‐mediated deficiency of cathepsin D results in FTD and NCL‐like phenotypes in neurons derived from FTD patients. Hum Mol Genet 26: 4861– 4872 29036611 PMC5886207
  69. Valdez C, Ysselstein D, Young TJ, Zheng J, Krainc D (2019) Progranulin mutations result in impaired processing of prosaposin and reduced glucocerebrosidase activity. Hum Mol Genet 29: 716– 726 PMC7104673 31600775
  70. Van Deerlin VM, Wood EM, Moore P, Yuan W, Forman MS, Clark CM, Neumann M, Kwong LK, Trojanowski JQ, Lee VM et al (2007) Clinical, genetic, and pathologic characteristics of patients with frontotemporal dementia and progranulin mutations. Arch Neurol 64: 1148– 1153 17698705
  71. Van Deerlin VM, Sleiman PM, Martinez‐Lage M, Chen‐Plotkin A, Wang LS, Graff‐Radford NR, Dickson DW, Rademakers R, Boeve BF, Grossman M et al (2010) Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP‐43 inclusions. Nat Genet 42: 234– 239 20154673 PMC2828525
  72. Ward ME, Taubes A, Chen R, Miller BL, Sephton CF, Gelfand JM, Minami S, Boscardin J, Martens LH, Seeley WW et al (2014) Early retinal neurodegeneration and impaired Ran‐mediated nuclear import of TDP‐43 in progranulin‐deficient FTLD. J Exp Med 211: 1937– 1945 25155018 PMC4172214
  73. Ward ME, Chen R, Huang HY, Ludwig C, Telpoukhovskaia M, Taubes A, Boudin H, Minami SS, Reichert M, Albrecht P et al (2017) Individuals with progranulin haploinsufficiency exhibit features of neuronal ceroid lipofuscinosis. Sci Transl Med 9: eaah5642 28404863 PMC5526610
  74. Werner G, Damme M, Schludi M, Gnörich J, Wind K, Fellerer K, Wefers B, Wurst W, Edbauer D, Brendel M et al (2020) Loss of TMEM106B potentiates lysosomal and FTD‐like pathology in progranulin deficient mice. EMBO Rep 10.15252/embr.202050241 PMC7534633 32929860 · DOI
  75. Wils H, Kleinberger G, Pereson S, Janssens J, Capell A, Van Dam D, Cuijt I, Joris G, De Deyn PP, Haass C et al (2012) Cellular ageing, increased mortality and FTLD‐TDP‐associated neuropathology in progranulin knockout mice. J Pathol 228: 67– 76 22733568
  76. Wood HB (2010) TMEM106B is a susceptibility locus for Ftld. Nat Rev Neurol 6: 184 20383883
  77. Xu HM, Tan L, Wan Y, Tan MS, Zhang W, Zheng ZJ, Kong LL, Wang ZX, Jiang T, Tan L et al (2017) PGRN is associated with Late‐onset Alzheimer's disease: a case‐control replication study and meta‐analysis. Mol Neurobiol 54: 1187– 1195 26820675
  78. 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 29444210
  79. Yin F, Banerjee R, Thomas B, Zhou P, Qian L, Jia T, Ma X, Ma Y, Iadecola C, Beal MF et al (2010a) Exaggerated inflammation, impaired host defense, and neuropathology in progranulin‐deficient mice. J Exp Med 207: 117– 128 20026663 PMC2812536
  80. van der Zee J, Van Broeckhoven C (2011) TMEM106B a novel risk factor for frontotemporal lobar degeneration. J Mol Neurosci 45: 516– 521 21614538 PMC3207134
  81. van der Zee J, Van Langenhove T, Kleinberger G, Sleegers K, Engelborghs S, Vandenberghe R, Santens P, Van den Broeck M, Joris G, Brys J et al (2011) TMEM106B is associated with frontotemporal lobar degeneration in a clinically diagnosed patient cohort. Brain 134: 808– 815 21354975 PMC3044834
  82. Zerbino DR, Achuthan P, Akanni W, Amode MR, Barrell D, Bhai J, Billis K, Cummins C, Gall A, Giron CG et al (2018) Ensembl 2018. Nucleic Acids Res 46: D754– D761 29155950 PMC5753206
  83. Zhou X, Sun L, Bastos de Oliveira F, Qi X, Brown WJ, Smolka MB, Sun Y, Hu F (2015) Prosaposin facilitates sortilin‐independent lysosomal trafficking of progranulin. J Cell Biol 210: 991– 1002 26370502 PMC4576858
  84. Zhou X, Paushter DH, Feng T, Pardon CM, Mendoza CS, Hu F (2017a) Regulation of cathepsin D activity by the FTLD protein progranulin. Acta Neuropathol 134: 151– 153 28493053 PMC5568051
  85. Zhou X, Paushter DH, Feng T, Sun L, Reinheckel T, Hu F (2017b) Lysosomal processing of progranulin. Mol Neurodegener 12: 62 28835281 PMC5569495
  86. Zhou X, Sun L, Bracko O, Choi JW, Jia Y, Nana AL, Brady OA, Hernandez JCC, Nishimura N, Seeley WW et al (2017c) Impaired prosaposin lysosomal trafficking in frontotemporal lobar degeneration due to progranulin mutations. Nat Commun 8: 15277 28541286 PMC5477518
  87. Zhou X, Sun L, Brady OA, Murphy KA, Hu F (2017d) Elevated TMEM106B levels exaggerate lipofuscin accumulation and lysosomal dysfunction in aged mice with progranulin deficiency. Acta Neuropathol Commun 5: 9 28126008 PMC5270347
  88. Zhou X, Paushter DH, Pagan MD, Kim D, Nunez Santos M, Lieberman RL, Overkleeft HS, Sun Y, Smolka MB, Hu F (2019) Progranulin deficiency leads to reduced glucocerebrosidase activity. PLoS ONE 14: e0212382 31291241 PMC6619604
  89. Zhou X, Brooks M, Jiang P, Koga S, Zuberi AR, Baker MC, Parsons TM, Castanedes‐Casey M, Phillips V, Librero AL et al (2020a) Loss of Tmem106b exacerbates FTLD pathologies and causes motor deficits in progranulin deficient mice. EMBO Rep 10.15252/embr.202050197 PMC7534638 32761777 · DOI
  90. Zhou X, Nicholson AM, Ren Y, Brooks M, Jiang P, Zuberi A, Phuoc HN, Perkerson RB, Matchett B, Parsons TM et al (2020b) Loss of TMEM106B leads to myelination deficits: implications for frontotemporal dementia treatment strategies. Brain 143: 1905– 1919 32504082 PMC7296855

Cited by

Sorted by citations

Authors
Feng, T., Mai, S., Roscoe, J. M., Sheng, R. R., Ullah, M., Zhang, J., Katz, I. I., Yu, H., Xiong, W., & Hu, F.
Affiliations
  • Cornell University (US)
  • City University of Hong Kong (HK)
Corresponding author
Hu, Fenghua
ORCID
Venue
The EMBO Reports
Publisher
Springer Science and Business Media LLC
Published
2020-08-10
Volume
21
Issue
10
Pages
e50219-e50219
ISSN
  • 1469-221X (ISSN-L)
  • 1469-3178
DOI
10.15252/embr.202050219
PMC
PMC7534636
OpenAlex
W3048097679
Cited by
94
References
11
Citations by year
2026: 8 · 2025: 15 · 2024: 26 · 2023: 14 · 2022: 14 · 2021: 13 · 2020: 4
FWCI
5.01
Type
journal article
Language
en
Open access
Licence
Locations
  • EMBO Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • CityU Scholars (submittedVersion, cc-by)
Funders
  • HHS|NIH | National Institute of Neurological Disorders and Stroke (NINDS); National Institute for Aging (R01NS088448, R01NS095954)
  • The Bluefield project to Cure FTD
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
Keywords
TMEM106B, progranulin, frontotemporal lobar degeneration, lysosomal dysfunction, axon initial segment, motor neurons, lysosomal vacuoles, neurodegeneration, brain aging, microglia, astrocytes, glial activation, neuronal loss, mouse model
MeSH terms
Progranulins, Animals, Lysosomes, Membrane Proteins, Nerve Tissue Proteins, Intercellular Signaling Peptides and Proteins, Mice, Frontotemporal Lobar Degeneration, Frontotemporal Dementia

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review