FTD Risk Factor Confirmed, Alters Progranulin Pathways

The case for transmembrane protein 106B being a genetic risk factor for frontotemporal dementia, as suggested two years ago, now looks more convincing. In the August 15 Journal of Neuroscience, a team from the University of Pennsylvania, in Philadelphia reports an overabundance of TMEM106B in the brains of people who died due to frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). They also discovered that TMEM106B-regulating microRNAs fail to reach normal concentrations in the frontotemporal dementia (FTD) brain samples. In addition, “we have our first clues as to how this protein and gene may be working,” said lead author Alice Chen-Plotkin. TMEM106B localizes to late endosomes and lysosomes, and too much of the protein may interfere with the cellular garbage disposal system there. Progranulin accumulates in cells with too much TMEM106B as well, linking what appeared to be two unrelated risk factors for FTD.

Previously, Chen-Plotkin and dozens of FTD researchers collaborated in a genomewide association study (GWAS) that pointed to a TMEM106B genetic variant (see ARF related news story on Van Deerlin et al., 2010). TMEM106B was the only gene in the neighborhood of the single nucleotide polymorphism associated with FTD, though with GWAS, “you never know,” Chen-Plotkin said. Some scientists remained skeptical because there were only 515 FTD samples in that study, and many had progranulin mutations that complicated interpretation, noted Julie van der Zee of Christine van Broeckhoven’s group at the VIB University of Antwerp, Belgium, in an e-mail to Alzforum. Van der Zee was an author on the GWAS paper but was not involved in the current study.

At that time, Chen-Plotkin—who started the newly published work in the University of Pennsylvania laboratory of Virginia Lee and completed it in her own lab—had another reason to trust the TMEM106B link. While screening the genome for risk alleles as part of the GWAS, she was also hunting for microRNA changes in frontal cortex samples. “I remember vividly when I analyzed all the microRNA data, and the top hit—of 800-plus candidates—was microRNA-132,” she said. It was a jaw-dropping moment, she recalled, once she realized microRNA-132 targeted the gene that just popped out of the GWAS, TMEM106B. With two independent screens pointing in the same direction, she and her colleagues felt they were truly on to something. Recent data from van Broeckhoven’s lab also supported TMEM106B’s role in FTD (van der Zee et al., 2011).

In reporting the GWAS, Chen-Plotkin and colleagues suggested that TMEM106B mRNA overexpression drives pathology in FTD. Here, they bolster their argument. Quantitative polymerase chain reaction confirmed more of the mRNA in the frontal cortex, temporal cortex, and occipital cortex of people with the disease, compared to normal controls. Interestingly, people with progranulin mutations expressed the most TMEM106B mRNA, and harbored more of the protein, than did controls or progranulin-negative cases. Using immunohistochemistry, Chen-Plotkin also observed that TMEM106B extended into neuronal processes in people with FTD, though the protein is normally found in the cell body.

The microRNAs come into the picture as repressors of TMEM106B expression. There are four members of the microRNA-132 family—miR-132, miR-212, miR-132*, and miR-212*; the last was not part of the microarray. MicroRNA-132 and -212 bind the TMEM106B 3’ untranslated region. All three microRNAs analyzed were down by more than half in frontal cortex samples from both progranulin-positive and -negative FTD cases. The three miRNAs all arise from the same pri-mRNA transcript, so the authors suspect that people with FTD may not make enough of the pri-mRNA. MicroRNA-132 and -212 are involved in neuron differentiation and inflammation, and have already been linked to several neurodegenerative conditions; the functions of microRNA-132* and -212* remain unknown (reviewed in Wanet et al., 2012).

What depresses the miRNAs and, hence, elevates TMEM106B remains to be determined. Researchers have not yet identified polymorphisms that presumably promote TMEM106B expression. The microRNA binding regions would be a good place to look, van der Zee suggested, as would the genes for these microRNAs themselves. Any way the cell produces too much TMEM106B is likely to be bad news, Chen-Plotkin said.

What makes TMEM106B so bad for cells? Chen-Plotkin confirmed that it localizes to late endosomes and lysosomes, as others reported (Lang et al., 2012), and when the researchers overexpressed the gene in a variety of human and mouse cells, they saw those TMEM106B-containing organelles swell. Moreover, when TMEM106B was overexpressed, these compartments became less acidic than normal. The low acidity could affect processing of many proteins, including progranulin, which moves through the endosome-lysosome system.

In fact, in cells overexpressing TMEM106B, normally diffused progranulin appeared as bright puncta, Chen-Plotkin said. When the researchers lysed the cells, they discovered higher intracellular progranulin concentrations in TMEM106B-overexpressing cultures than controls cells. The results suggest that altered trafficking of progranulin, a facet of FTD due to progranulin mutations, contributes to other cases as well. It is also possible that progranulin and TMEM106B mutations may act synergistically: In people carrying a progranulin mutation and the TMEM106B risk variant, the disease appears 13 years earlier than normal, according to one study (Cruchaga et al., 2011).

The work “provides compelling mechanistic evidence for a true involvement of TMEM106B in the disease pathway of FTLD-TDP,” van der Zee wrote. But it leaves open the question of how, exactly, TMEM106B contributes. “My guess is it has to do with endosomal pathway function,” Chen-Plotkin said, adding that if she knew more than that, she would rechristen the gene with a more descriptive name.—Amber Dance

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References

News Citations

  1. Genetics of FTD: New Gene, PGRN Variety, and a Bit of FUS

Paper Citations

  1. 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.
  2. 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, Mattheijssens M, Peeters K, Cras P, De Deyn PP, Cruts M, Van Broeckhoven C. TMEM106B is associated with frontotemporal lobar degeneration in a clinically diagnosed patient cohort. Brain. 2011 Mar;134(Pt 3):808-15. PubMed.
  4. Lang CM, Fellerer K, Schwenk BM, Kuhn PH, Kremmer E, Edbauer D, Capell A, Haass C. Membrane Orientation and Subcellular Localization of Transmembrane Protein 106B (TMEM106B), a Major Risk Factor for Frontotemporal Lobar Degeneration. J Biol Chem. 2012 Jun 1;287(23):19355-65. PubMed.
  5. Cruchaga C, Graff C, Chiang HH, Wang J, Hinrichs AL, Spiegel N, Bertelsen S, Mayo K, Norton JB, Morris JC, Goate A. Association of TMEM106B gene polymorphism with age at onset in granulin mutation carriers and plasma granulin protein levels. Arch Neurol. 2011 May;68(5):581-6. PubMed.

Further Reading

Papers

  1. van der Zee J, Van Broeckhoven C. TMEM106B a novel risk factor for frontotemporal lobar degeneration. J Mol Neurosci. 2011 Nov;45(3):516-21. PubMed.
  2. Rollinson S, Mead S, Snowden J, Richardson A, Rohrer J, Halliwell N, Usher S, Neary D, Mann D, Hardy J, Pickering-Brown S. Frontotemporal lobar degeneration genome wide association study replication confirms a risk locus shared with amyotrophic lateral sclerosis. Neurobiol Aging. 2011 Apr;32(4):758.e1-7. PubMed.
  3. Finch N, Carrasquillo MM, Baker M, Rutherford NJ, Coppola G, Dejesus-Hernandez M, Crook R, Hunter T, Ghidoni R, Benussi L, Crook J, Finger E, Hantanpaa KJ, Karydas AM, Sengdy P, Gonzalez J, Seeley WW, Johnson N, Beach TG, Mesulam M, Forloni G, Kertesz A, Knopman DS, Uitti R, White CL, Caselli R, Lippa C, Bigio EH, Wszolek ZK, Binetti G, Mackenzie IR, Miller BL, Boeve BF, Younkin SG, Dickson DW, Petersen RC, Graff-Radford NR, Geschwind DH, Rademakers R. TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers. Neurology. 2011 Feb 1;76(5):467-74. PubMed.
  4. Rutherford NJ, Carrasquillo MM, Li M, Bisceglio G, Menke J, Josephs KA, Parisi JE, Petersen RC, Graff-Radford NR, Younkin SG, Dickson DW, Rademakers R. TMEM106B risk variant is implicated in the pathologic presentation of Alzheimer disease. Neurology. 2012 Aug 14;79(7):717-8. PubMed.
  5. 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.

Primary Papers

  1. Chen-Plotkin AS, Unger TL, Gallagher MD, Bill E, Kwong LK, Volpicelli-Daley L, Busch JI, Akle S, Grossman M, Van Deerlin V, Trojanowski JQ, Lee VM. TMEM106B, the risk gene for frontotemporal dementia, is regulated by the microRNA-132/212 cluster and affects progranulin pathways. J Neurosci. 2012 Aug 15;32(33):11213-27. PubMed.

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