Comments

1. • Markus Damme
     University of Kiel
   • Posted: 11 Mar 2021

   Variants in TMEM106B, coding for a lysosomal transmembrane protein, were recognized as important genetic modifiers in different neurodegenerative diseases and, in particular, in FTD patients harboring GRN mutations.

   Now, TMEM106B comes into the spotlight for a disease that has changed our lives for more than one year: COVID-19. With outstanding reproducibility, three elegant, independent studies identified TMEM106B in unbiased genome-wide CRISPR knockout screens as a crucial host factor for SARS-CoV-2 infection: Cells lacking TMEM106B can hardly be infected with the nasty virus.

   A critical question, now, is what makes TMEM106B so essential for the virus. Many viruses bind to the extracellular domain of plasma-membrane-bound receptors and bind a second intracellular receptor upon endocytosis. Examples include the lysosomal membrane protein LAMP1 for the Lassa virus, NPC1 for the Ebola virus, or Scarb2 for Enterovirus 71. Future work is needed to determine if SARS-CoV-2 is hijacking TMEM106B for binding in lysosomes after being released from ACE2 upon endocytosis. In this regard, it should be mentioned that β-coronaviruses utilize lysosomal trafficking for egress rather than the biosynthetic secretory pathway more commonly used by other enveloped viruses (Ghosh et al., 2020). 

   Other scenarios are also feasible: Other hits identified in the screens include genes that play essential functions in autophagy (TMEM41B, CCZ1B) and lysosomal (VAC14) acidification, processes in which TMEM106B was also previously shown to be involved (Werner et al., 2020; Lüningschrör et al., 2020; Klein et al., 2017). These questions will be of major importance for future work and possibly developing TMEM106B-targeted therapies for COVID-19, e.g., by using monoclonal antibodies.

   The interesting question is if genetic variants/SNPs in TMEM106B influence infectivity, e.g., in patients harboring the protective coding SNP in the luminal domain that likely gets in direct contact with the virus. Major differences in disease severity in COVID-19 are well known, and it might be interesting to figure out if there is any direct correlation between the SNPs and disease severity. It might also be interesting to see if FTD-patients are more prone to a severe course of COVID-19.

   References:

   Ghosh S, Dellibovi-Ragheb TA, Kerviel A, Pak E, Qiu Q, Fisher M, Takvorian PM, Bleck C, Hsu VW, Fehr AR, Perlman S, Achar SR, Straus MR, Whittaker GR, de Haan CA, Kehrl J, Altan-Bonnet G, Altan-Bonnet N. β-Coronaviruses Use Lysosomes for Egress Instead of the Biosynthetic Secretory Pathway. Cell. 2020 Dec 10;183(6):1520-1535.e14. Epub 2020 Oct 27 PubMed.

   Werner G, Damme M, Schludi M, Gnörich J, Wind K, Fellerer K, Wefers B, Wurst W, Edbauer D, Brendel M, Haass C, Capell A. Loss of TMEM106B potentiates lysosomal and FTLD-like pathology in progranulin-deficient mice. EMBO Rep. 2020 Oct 5;21(10):e50241. Epub 2020 Sep 14 PubMed.

   Lüningschrör P, Werner G, Stroobants S, Kakuta S, Dombert B, Sinske D, Wanner R, Lüllmann-Rauch R, Wefers B, Wurst W, D'Hooge R, Uchiyama Y, Sendtner M, Haass C, Saftig P, Knöll B, Capell A, Damme M. The FTLD Risk Factor TMEM106B Regulates the Transport of Lysosomes at the Axon Initial Segment of Motoneurons. Cell Rep. 2020 Mar 10;30(10):3506-3519.e6. PubMed.

   Klein ZA, Takahashi H, Ma M, Stagi M, Zhou M, Lam TT, Strittmatter SM. Loss of TMEM106B Ameliorates Lysosomal and Frontotemporal Dementia-Related Phenotypes in Progranulin-Deficient Mice. Neuron. 2017 Jul 19;95(2):281-296.e6. PubMed.

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2. • Hyun-Sik Yang
     Brigham and Women's Hospital / Massachusetts General Hospital / Harvard Medical School
   • Posted: 11 Mar 2021

   TMEM106B first came under the scientific spotlight as a risk gene for frontotemporal lobar degeneration-TDP-43 (FTLD-TDP) (Van Deerlin et al., 2010), but the gene’s clinical implication goes beyond TDP-43 proteinopathy.

   A common TMEM106B haplotype tagged by a missense coding variant, rs3173615^C (TMEM106B p.S185T), increases risk of FTLD-TDP (Pottier et al., 2018; Van Deerlin et al., 2010) and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) (Yu et al., 2015). Moreover, this locus predicts cognitive impairment in other neurodegenerative disorders, such as amyotrophic lateral sclerosis (Vass et al., 2011) and Parkinson’s disease (Tropea et al., 2019), and is associated with poor cognitive resilience to neuropathology in older adults (White et al., 2017; Yang et al., 2020). Further, the same haplotype has a pleiotropic effect on other diseases and clinical traits, such as major depressive disorder (Wray et al., 2018) and higher triglyceride level (Klarin et al., 2018). Finally, a rare dominant missense mutation in TMEM106B (TMEM106B p.D252N) causes hypomyelinating leukodystrophy, an early onset disorder distinct from TDP-43 proteinopathies (Simons et al., 2017). 

   The three studies discussed here demonstrate that TMEM106B is an essential host protein for SARS-CoV2 infection, expanding the ever-growing list of TMEM106’s pleiotropic roles in human health and diseases. Baggen et al. found that TMEM106B knockout prevented SARS-CoV2 infection, which would be consistent with TMEM106B’s role in viral entry. In addition, COVID-19 patient-derived respiratory epithelial cells (from bronchoalveolar lavage) showed increased TMEM106B expression. These are intriguing observations that might hint at a shared pathophysiology between TDP-43 proteinopathy and viral infection, given accumulating evidence supporting that the TMEM106B FTLD-TDP risk haplotype leads to enhanced TMEM106B function, lysosomal dysfunction, and increased abnormal TDP-43 protein accumulation (e.g., Yang et al., 2020). 

   Nonetheless, it is important to note that we cannot make any direct clinical connections between COVID-19 and TDP-43 proteinopathy from this study, given the clear differences in disease pathophysiology, target organs, and experimental approaches. For example, this study does not tell us whether FTD patients or TMEM106B TDP-43 risk allele carriers would be more susceptible to SARS-CoV2 infection or severe COVID-19.

   Rather, a key message from this study to our field is that TMEM106B is a pleiotropic gene that has versatile physiologic roles in multiple biological processes, which raises a concern that systemic perturbation of TMEM106B to treat TDP-43 proteinopathy could lead to various off-target effects. Therefore, to target TMEM106B in TDP-43 proteinopathy clinical trials, it is critical to further understand the gene’s normal physiological function in various tissues beyond brain.

   References:

   Klarin D, Damrauer SM, Cho K, Sun YV, Teslovich TM, Honerlaw J, Gagnon DR, DuVall SL, Li J, Peloso GM, Chaffin M, Small AM, Huang J, Tang H, Lynch JA, Ho YL, Liu DJ, Emdin CA, Li AH, Huffman JE, Lee JS, Natarajan P, Chowdhury R, Saleheen D, Vujkovic M, Baras A, Pyarajan S, Di Angelantonio E, Neale BM, Naheed A, Khera AV, Danesh J, Chang KM, Abecasis G, Willer C, Dewey FE, Carey DJ, Global Lipids Genetics Consortium, Myocardial Infarction Genetics (MIGen) Consortium, Geisinger-Regeneron DiscovEHR Collaboration, VA Million Veteran Program, Concato J, Gaziano JM, O'Donnell CJ, Tsao PS, Kathiresan S, Rader DJ, Wilson PW, Assimes TL. Genetics of blood lipids among ~300,000 multi-ethnic participants of the Million Veteran Program. Nat Genet. 2018 Nov;50(11):1514-1523. Epub 2018 Oct 1 PubMed.

   Pottier C, Zhou X, Perkerson RB 3rd, Baker M, Jenkins GD, Serie DJ, Ghidoni R, Benussi L, Binetti G, López de Munain A, Zulaica M, Moreno F, Le Ber I, Pasquier F, Hannequin D, Sánchez-Valle R, Antonell A, Lladó A, Parsons TM, Finch NA, Finger EC, Lippa CF, Huey ED, Neumann M, Heutink P, Synofzik M, Wilke C, Rissman RA, Slawek J, Sitek E, Johannsen P, Nielsen JE, Ren Y, van Blitterswijk M, DeJesus-Hernandez M, Christopher E, Murray ME, Bieniek KF, Evers BM, Ferrari C, Rollinson S, Richardson A, Scarpini E, Fumagalli GG, Padovani A, Hardy J, Momeni P, Ferrari R, Frangipane F, Maletta R, Anfossi M, Gallo M, Petrucelli L, Suh E, Lopez OL, Wong TH, van Rooij JG, Seelaar H, Mead S, Caselli RJ, Reiman EM, Noel Sabbagh M, Kjolby M, Nykjaer A, Karydas AM, Boxer AL, Grinberg LT, Grafman J, Spina S, Oblak A, Mesulam MM, Weintraub S, Geula C, Hodges JR, Piguet O, Brooks WS, Irwin DJ, Trojanowski JQ, Lee EB, Josephs KA, Parisi JE, Ertekin-Taner N, Knopman DS, Nacmias B, Piaceri I, Bagnoli S, Sorbi S, Gearing M, Glass J, Beach TG, Black SE, Masellis M, Rogaeva E, Vonsattel JP, Honig LS, Kofler J, Bruni AC, Snowden J, Mann D, Pickering-Brown S, Diehl-Schmid J, Winkelmann J, Galimberti D, Graff C, Öijerstedt L, Troakes C, Al-Sarraj S, Cruchaga C, Cairns NJ, Rohrer JD, Halliday GM, Kwok JB, van Swieten JC, White CL 3rd, Ghetti B, Murell JR, Mackenzie IR, Hsiung GR, Borroni B, Rossi G, Tagliavini F, Wszolek ZK, Petersen RC, Bigio EH, Grossman M, Van Deerlin VM, Seeley WW, Miller BL, Graff-Radford NR, Boeve BF, Dickson DW, Biernacka JM, Rademakers R. 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. 2018 Jun;17(6):548-558. Epub 2018 Apr 30 PubMed.

   Simons C, Dyment D, Bent SJ, Crawford J, D'Hooghe M, Kohlschütter A, Venkateswaran S, Helman G, Poll-The BT, Makowski CC, Ito Y, Kernohan K, Hartley T, Waisfisz Q, Taft RJ, Care4Rare Consortium, van der Knaap MS, Wolf NI. A recurrent de novo mutation in TMEM106B causes hypomyelinating leukodystrophy. Brain. 2017 Dec 1;140(12):3105-3111. PubMed.

   Tropea TF, Mak J, Guo MH, Xie SX, Suh E, Rick J, Siderowf A, Weintraub D, Grossman M, Irwin D, Wolk DA, Trojanowski JQ, Van Deerlin V, Chen-Plotkin AS. TMEM106B Effect on cognition in Parkinson disease and frontotemporal dementia. Ann Neurol. 2019 Jun;85(6):801-811. PubMed.

   Van Deerlin VM, Sleiman PM, Martinez-Lage M, Chen-Plotkin A, Wang LS, Graff-Radford NR, Dickson DW, Rademakers R, Boeve BF, Grossman M, Arnold SE, Mann DM, Pickering-Brown SM, Seelaar H, Heutink P, van Swieten JC, Murrell JR, Ghetti B, Spina S, Grafman J, Hodges J, Spillantini MG, Gilman S, Lieberman AP, Kaye JA, Woltjer RL, Bigio EH, Mesulam M, Al-Sarraj S, Troakes C, Rosenberg RN, White CL, Ferrer I, Lladó A, Neumann M, Kretzschmar HA, Hulette CM, Welsh-Bohmer KA, Miller BL, Alzualde A, Lopez de Munain A, McKee AC, Gearing M, Levey AI, Lah JJ, Hardy J, Rohrer JD, Lashley T, Mackenzie IR, Feldman HH, Hamilton RL, Dekosky ST, van der Zee J, Kumar-Singh S, Van Broeckhoven C, Mayeux R, Vonsattel JP, Troncoso JC, Kril JJ, Kwok JB, Halliday GM, Bird TD, Ince PG, Shaw PJ, Cairns NJ, Morris JC, McLean CA, Decarli C, Ellis WG, Freeman SH, Frosch MP, Growdon JH, Perl DP, Sano M, Bennett DA, Schneider JA, Beach TG, Reiman EM, Woodruff BK, Cummings J, Vinters HV, Miller CA, Chui HC, Alafuzoff I, Hartikainen P, Seilhean D, Galasko D, Masliah E, Cotman CW, Tuñón MT, Martínez MC, Munoz DG, Carroll SL, Marson D, Riederer PF, Bogdanovic N, Schellenberg GD, Hakonarson H, Trojanowski JQ, Lee VM. Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions. Nat Genet. 2010 Mar;42(3):234-9. PubMed.

   Vass R, Ashbridge E, Geser F, Hu WT, Grossman M, Clay-Falcone D, Elman L, McCluskey L, Lee VM, Van Deerlin VM, Trojanowski JQ, Chen-Plotkin AS. Risk genotypes at TMEM106B are associated with cognitive impairment in amyotrophic lateral sclerosis. Acta Neuropathol. 2011 Mar;121(3):373-80. PubMed.

   White CC, Yang HS, Yu L, Chibnik LB, Dawe RJ, Yang J, Klein HU, Felsky D, Ramos-Miguel A, Arfanakis K, Honer WG, Sperling RA, Schneider JA, Bennett DA, De Jager PL. Identification of genes associated with dissociation of cognitive performance and neuropathological burden: Multistep analysis of genetic, epigenetic, and transcriptional data. PLoS Med. 2017 Apr;14(4):e1002287. Epub 2017 Apr 25 PubMed.

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   Yang HS, White CC, Klein HU, Yu L, Gaiteri C, Ma Y, Felsky D, Mostafavi S, Petyuk VA, Sperling RA, Ertekin-Taner N, Schneider JA, Bennett DA, De Jager PL. Genetics of Gene Expression in the Aging Human Brain Reveal TDP-43 Proteinopathy Pathophysiology. Neuron. 2020 Aug 5;107(3):496-508.e6. Epub 2020 Jun 10 PubMed.

   Yu L, De Jager PL, Yang J, Trojanowski JQ, Bennett DA, Schneider JA. The TMEM106B locus and TDP-43 pathology in older persons without FTLD. Neurology. 2015 Mar 3;84(9):927-34. Epub 2015 Feb 4 PubMed.

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References

News Citations

1. Nixing TMEM106b Fans the Flames of Progranulin Deficiency 25 Sep 2020
2. Without TMEM106B, Lysosomal Traffic Jams Wreak Havoc in Neurons 11 Mar 2020
3. Massive GWAS Meta-Analysis Digs Up Trove of Alzheimer’s Genes 24 Feb 2021
4. TMEM106B Variants Regulate Gene Modules, TDP-43 Pathology 12 Jun 2020

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