30 Jan 2024

Variants in the TMEM106b gene influence the risk and severity of frontotemporal dementia, but how? A study published January 17 in Science Translational Medicine suggests that the answer comes down to the lysosomal protein’s propensity to twist into fibrils. Equipped with a new antibody trained against a sequence exposed on the surface of TMEM106b filaments, researchers led by Mercedes Prudencio, Leonard Petrucelli, and Casey Cook at the Mayo Clinic in Jacksonville, Florida, found that while a protective variant squelched filament formation, a risk variant at the same nucleotide egged it on. In people with FTD-TDP-43, this stepped up aggregation of TMEM106b, correlated with worse TDP-43 dysfunction, and a faster course of disease. The findings suggest that while TMEM106b filament formation may not in itself cause FTD, it can accelerate the disease for those already on its path.

“Genetic variation at the TMEM106B locus is a massively underappreciated risk factor for dementia, with a large impact on public health,” commented Peter Nelson of the University of Kentucky in Lexington. The new study emphasizes Nelson's point in the context of FTD, and offers new insights into the mechanisms involved. The study could have implications for other TDP-43 proteinopathies, such as limbic predominant TDP-43 encephalopathy (LATE), a more common condition in which TMEM106b variants also appear to play a part.

Carriers of pathogenic mutations in the GRN and C9ORF27 genes face high odds of developing FTD-TDP-43, but their age at onset, or indeed, whether they get the disease at all, is subject to variation TMEM106b. Researchers long ago tied differences at a single nucleotide within TMEM106b to disease risk and severity among these pathogenic mutation carriers (Feb 2010 news on Van Deerlin et al., 2011; Cruchaga et al., 2011; Aug 2012 news). A rare protective variant at the same SNP did the opposite, delaying age at onset, lessening TDP-43 pathology, and slowing progression (Gallagher et al., 2014; van Blitterswijk et al., 2014).

Since then, the mystery has been how TMEM106b influences FTD risk and progression. They think they know where this happens: in the endolysosomal system, where TMEM106b and other FTD-related gene products mingle (Sep 2020 news; Sep 2023 news).

The plot thickened in 2022, when a trio of studies discovered TMEM106b filaments lurking not only in the brains of people with FTD, but also among cognitively normal people over the age of 50 (Apr 2022 news).

Could TMEM106b fibrillization be the conduit for its effect on TDP-43 pathology and disease risk? Co-first authors Jordan Marks, Virginia Ayuso, Yari Carlomagno and colleagues set out to answer the question. First, they investigated the relationship between TMEM106b haplotype and disease severity among 228 people in the Mayo Clinic Brain bank cohort who had died with FTD-TDP-43. Eighteen homozygous carriers of the protective allele, which encodes the serine-185 variant of TMEM106b, lived for an average of 12 years following diagnosis. This is compared to an eight-year survival among the 210 people who carried one or two copies of the threonine-185- encoding risk allele.

Next, using published cryo-EM structures of TMEM106b fibrils as a guide, the scientists developed an antibody against a stretch of amino acids reportedly exposed on the surface of the filaments, which themselves are wound with a C-terminal fragment of the protein. Within the insoluble fraction of brain extracts from people with FTD-TDP, the antibody labeled a 29kDa band thought to represent TMEM106b fibrils. This insoluble species was abundant in risk variant carriers, yet hardly detectable among homozygous carriers of the protective variant. This was also true among cognitively normal people. The T185-variant therefore appeared more prone to fibrillization than its protective, S185 counterpart.

Flagging a Fibril. A new TMEM106b antibody was developed that recognizes a stretch of amino acids exposed on the surface of fibrils (blue, left). The antibody latched onto fibrils, as seen by immuno-electron microscopy (right). [Courtesy of Marks et al., Science Translational Medicine, 2024.]

To see if TMEM106b’s fibrillization influences TDP-43 pathology FTD, the scientists checked for correlations between the abundance of fibrillar TMEM106b and that of aggregates of phosphorylated TDP-43. Sure enough, the two were linked. The TMEM106b fibrils also tracked with truncated transcripts of stathmin-2, which needs TDP-43 for proper splicing.

To the authors, the findings suggest that TMEM106b aggregation somehow exacerbates TDP-43 accumulation and dysfunction. This could explain why the protective genotype comes with longer survival after symptoms start.

To edge closer toward the mechanism linking TMEM106b to TDP-43, the researchers surveyed the posse of proteins that mingled with TMEM106b fibrils in brain extracts. TDP-43, along with many of its known substrates, was among insoluble TMEM’s 1,309 protein partners, as were proteins involved in translation, intracellular transport, and endocytosis. Proteins implicated in neurodegenerative disease, including TBK1, optineurin, VCP, and huntingtin, were also among TMEM’s associates. Cook told Alzforum that this interactome will inform future studies to find out how TMEM106b aggregation influences disease risk and pathology.

For now, Cook and Prudencio hypothesize that aggregated TMEM106b ensnares other proteins, preventing them from doing their jobs. Interestingly, despite TMEM106b’s status as a lysosomal protein, many of its interactors are not. The authors speculated that, particularly in the context of pathogenic GRN mutations that compromise the integrity of lysosomes, perhaps TMEM106b fibrils leak out into the cytoplasm where they buddy up with other proteins. Along these lines, previous studies indicate that endolysosomal dysfunction instigates TDP-43 pathology (Oct 2022 news).—Jessica Shugart

Comments

1. • Peter Nelson
     University of Kentucky
   • Posted: 30 Jan 2024

   Genetic variation at the TMEM106B locus is a massively under-appreciated risk factor for dementia, with a large impact on public health. TMEM106B variance was identified as a genetic modifier of dementia risk in the context of FTLD/FTD, as re-emphasized with new insights by the strong, recently published work by Jordan Marks and colleagues.

   FTLD/FTD is a ~1:1,000 lifetime risk disease that often affects persons in advanced middle age, and each case is a tragedy.  Moreover, TMEM106B (predicated on the same risk allele) also appears to stimulate TDP-43 proteinopathy in the far more prevalent condition limbic-predominant age-related TDP-43 encephalopathy (LATE)—a 1 in 3 lifetime risk disease that usually affects older persons. 

   Another interesting thing about the disease-driving TMEM106B haplotype: it appears to be differently inherited in persons of different ethnoracial backgrounds.  For example, in persons with European ancestry, the risk allele is actually represented in the majority (more white people are at risk from TMEM106B genotype than are not at risk), whereas in persons of African ancestry the TMEM106B risk allele is in the minority. 

   By contrast, the other important risk factor for LATE-NC (GRN gene variant rs5848) is far more common in persons with African ancestry than in persons of European ancestry (Katsumata et al., 2023).  These observations, coupled with the large apparent impact of these alleles, suggest that future therapeutic strategies for FTLD/FTD and LATE-NC may have some differences based on the patient populations that are being served.

   References:

   Katsumata Y, Fardo DW, Shade LM, Alzheimer’s Disease Genetics Consortium, Nelson PT. LATE-NC risk alleles (in TMEM106B, GRN, and ABCC9 genes) among persons with African ancestry. J Neuropathol Exp Neurol. 2023 Aug 21;82(9):760-768. PubMed.

   View all comments by Peter Nelson

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References

News Citations

1. Genetics of FTD: New Gene, PGRN Variety, and a Bit of FUS 17 Feb 2010
2. FTD Risk Factor Confirmed, Alters Progranulin Pathways 24 Aug 2012
3. Nixing TMEM106b Fans the Flames of Progranulin Deficiency 25 Sep 2020
4. Endolysosomal TMEM106b Regulates Myelin Lipid Metabolism 27 Sep 2023
5. Surprise! TMEM106b Fibrils Found in Neurodegenerative Diseases 12 Apr 2022
6. ALS/FTD Genes Converge on Endolysosomal System, Stoking TDP-43 Pathology 18 Oct 2022

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. 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.
3. Gallagher MD, Suh E, Grossman M, Elman L, McCluskey L, Van Swieten JC, Al-Sarraj S, Neumann M, Gelpi E, Ghetti B, Rohrer JD, Halliday G, Van Broeckhoven C, Seilhean D, Shaw PJ, Frosch MP, Alafuzoff I, Antonell A, Bogdanovic N, Brooks W, Cairns NJ, Cooper-Knock J, Cotman C, Cras P, Cruts M, De Deyn PP, DeCarli C, Dobson-Stone C, Engelborghs S, Fox N, Galasko D, Gearing M, Gijselinck I, Grafman J, Hartikainen P, Hatanpaa KJ, Highley JR, Hodges J, Hulette C, Ince PG, Jin LW, Kirby J, Kofler J, Kril J, Kwok JB, Levey A, Lieberman A, Llado A, Martin JJ, Masliah E, McDermott CJ, McKee A, McLean C, Mead S, Miller CA, Miller J, Munoz DG, Murrell J, Paulson H, Piguet O, Rossor M, Sanchez-Valle R, Sano M, Schneider J, Silbert LC, Spina S, van der Zee J, Van Langenhove T, Warren J, Wharton SB, White CL 3rd, Woltjer RL, Trojanowski JQ, Lee VM, Van Deerlin V, Chen-Plotkin AS. TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions. Acta Neuropathol. 2014 Mar;127(3):407-18. Epub 2014 Jan 19 PubMed.
4. van Blitterswijk M, Mullen B, Nicholson AM, Bieniek KF, Heckman MG, Baker MC, DeJesus-Hernandez M, Finch NA, Brown PH, Murray ME, Hsiung GY, Stewart H, Karydas AM, Finger E, Kertesz A, Bigio EH, Weintraub S, Mesulam M, Hatanpaa KJ, White CL 3rd, Strong MJ, Beach TG, Wszolek ZK, Lippa C, Caselli R, Petrucelli L, Josephs KA, Parisi JE, Knopman DS, Petersen RC, Mackenzie IR, Seeley WW, Grinberg LT, Miller BL, Boylan KB, Graff-Radford NR, Boeve BF, Dickson DW, Rademakers R. TMEM106B protects C9ORF72 expansion carriers against frontotemporal dementia. Acta Neuropathol. 2014 Mar;127(3):397-406. Epub 2014 Jan 3 PubMed.

Further Reading

News

1. TMEM106B Variants Regulate Gene Modules, TDP-43 Pathology 12 Jun 2020