Endolysosomal TMEM106b Regulates Myelin Lipid Metabolism

Variants of TMEM106b are tied to frontotemporal dementia and Alzheimer’s disease, but how the endolysosomal protein provokes pathology is unknown. Perhaps by perturbing myelin, suggest researchers led by Stephen Strittmatter, Yale University School of Medicine, New Haven, Connecticut. In a bioRxiv preprint posted September 14, they reported that mice deficient in TMEM106b have less of the myelin lipid galactosylceramide. Galactosylceramidase (GALC), the enzyme that hydrolyzes the lipid, is more active in the TMEM106b-deficient animals. The scientists suspect that TMEM106b binds to GALC, preventing it from breaking down the lipids that insulate axons. Ultimately, this may preserve neuron function.

Scientists know little about what TMEM106b does in endolysosomes or how the protein loses function during disease. TMEM106b fibrils have been found in the brains of people who had FTD and AD, but whether those aggregates explain TMEM106b mutations that increase the risk of either disease is unclear (Apr 2022 news; Feb 2021 news; Sep 2021 news).

To learn more about the protein, first author Hideyuki Takahashi studied what happens in its absence. He and others in Strittmatter’s lab had previously created TMEM106b-deficient mice via gene-trap mutagenesis, whereby they inserted the LacZ gene into the TMEM106b gene, disrupting its expression (Klein et al., 2017; Perez-Canamas et al., 2021). The mice express 5 to 10 percent of the usual amount of the protein.

Takahashi isolated the brains of 12-month-old TMEM106b-deficient and wild-type mice, homogenized the tissue, and measured lipid content by mass spectrometry. Why lipids? Because their metabolism becomes dysregulated in FTD, and Takahashi had a hunch that TMEM106b might be involved (Boland et al., 2022; Sep 2017 news). A missense mutation in the protein causes hypomyelinating leukodystrophy, a neurodevelopmental disorder caused by myelin deficits, potentially linking dysfunction of TMEM106b to myelin diseases (Simons et al., 2017).

How did lipids change without TMEM106b? Among the most downregulated were species of cerebrosides and sulfatides, specifically galactosylceramides and their sulfatide derivatives (see image below). These glycolipids caught the researchers’ attention because they are a primary part of the myelin sheath (Boggs 2014; reviewed by Grassi et al., 2016). Other components include cholesterol, phospholipids, and other glycolipids (reviewed by Kister and Kister, 2022). 

Muted Myelin. Mice deficient in TMEM106b downregulated multiple cerebrosides (red dots) and sulfatides (orange dots) in their brains compared to wild-type animals. [Courtesy of Takahashi et al., bioRxiv, 2023.]

To see how TMEM106b might cause these lipid changes, Takahashi immunoprecipitated it, and any proteins clinging to it, from the mouse brain homogenates, then analyzed the proteins using mass spectrometry. He found 22 TMEM106b binding partners, including a few previously reported ones, such as cathepsin D and vacuolar ATPase (Sep 2020 news; Jul 2017 news).

Galactosylceramidase ranked high among TMEM106b’s suitors. Within lysosomes GALC removes the galactose from galactosylceramides, offering a mechanistic link between the lipid and TMEM106b. In brain tissue from TMEM106b-deficient mice, GALC metabolized 10 to 15 percent more substrate than it did in wild-type tissue. To the authors, these results suggest that without TMEM106, GALC is more active, compromising myelin lipids.

However, the scientists don’t know how the two proteins interact. “Does TMEM106b modulate GALC’s activity? Its stability? Its transport to lysosomes?” asked Markus Damme, University of Kiel, Germany (comment below).

Takahashi and colleagues have not tested those scenarios, but they think their findings have implications for TMEM106b-linked diseases. “Our results could explain how a mutation in TMEM106b leads to hypomyelinating leukodystrophy,” they wrote, since less TMEM106b would leave GALC to run wild and gobble myelin lipid. They also think these data help explain some white-matter abnormalities seen in AD and disrupted myelin lipid metabolism in FTD (Bartzokis et al., 2003; Marian et al., 2023). In fact, Anthony Don, University of Sydney, Australia, and colleagues found that a TMEM106b variant, which increases risk of FTD and AD, correlated with less myelin sulfatides and hexosylceramides, which include galactosylceramide, in hippocampal tissue from healthy older adults (Lee et al., 2023) “Takahashi et al.’s results seem to fit with a large body of evidence that gene variants associated with dementia, particularly FTD, affect lysosomal catabolism of myelin lipids,” Don wrote.—Chelsea Weidman Burke

Comments

  1. A point mutation in TMEM106B causes a rare form of hypomyelinating leukodystrophy (HLD) (Simons et al., 2017), but how it does so is unknown. Therefore, it is critical to understand TMEM106b’s physiological function. It was speculated from the AlphaFold-predicted structure of TMEM106B that the luminal domain could be a lipid-binding or lipid-transfer protein, and here Takahashi et al. from Stephen Strittmatter's group performed an interesting study to address the physiological function of TMEM106B: They applied a lipidomics screen in Tmem106b knockout mice and found changes in major myelin lipids including galactosylceramide (GalCer). Interestingly, they found a physical interaction of TMEM106B with galactosylceramidase (GALC), a critical enzyme that acts in the lysosomal breakdown of galactosylceramide.

    Though this interesting study has some shortcomings and limitations, it provokes further questions. The group used a hypomorphic mouse model that expresses some residual TMEM106B due to the gene-trap targeting approach (Perez-Canamas et al., 2021), and it cannot be ruled out that the residual protein affects the outcome. In the Grn knockout mice, for example, the Strittmatter hypomorphic Tmem106b mouse improved the phenotype (Klein et al., 2017), while the full TMEM106b knockout drastically aggravated it, as shown by three other groups (Werner et al., 2020; Zhou et al., 2020; Feng et al., 2020). This clearly shows how relevant a little amount of TMEM106B can be.

    Here, the observed lipid changes seem to be very minor, and it remains to be seen if this decrease is relevant for any myelination phenotypes. Notably, other groups mostly saw myelination defects in challenged de-myelination and remyelination models in full Tmem106b knockout mice (Feng et al., 2020; Zhou et al., 2020). In line with changes in GalCer, the authors found a physical interaction between the luminal domain of TMEM106B and GALC, the enzyme that degrades GalCer in lysosomes. However, it is not clear how TMEM106B and GALC interact, or how TMEM106B affects GALC: Does it modulate its activity? Its stability? Its transport to lysosomes? In total brain of the hypomorphic mice the GALC enzymatic activity is increased, but that does not necessarily explain the reduced GalCer, which is rare in lysosomes and mostly found in the myelin sheath of oligodendrocytes. Further work is needed to clarify how the TMEM106B-GALC interaction, the lysosomal turnover of GalCer, and myelination, relate to each other functionally.

    Finally, the relevance of TMEM106B genetic variants T186S and D253N to GALC/GalCer should be examined. This might help explain how the findings relate to the protective effect of TMEM106B in FTLD and other neurodegenerative diseases. Notably, in another very recent study on human material, TMEM106B genotype correlated with low levels of myelin lipids in the hippocampus, including hexosylceramide (Lee et al., 2023). Further understanding is urgently needed.

    References:

    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.

    Perez-Canamas A, Takahashi H, Lindborg JA, Strittmatter SM. Fronto-temporal dementia risk gene TMEM106B has opposing effects in different lysosomal storage disorders. Brain Commun. 2021;3(1):fcaa200. Epub 2020 Nov 16 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.

    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.

    Zhou X, Brooks M, Jiang P, Koga S, Zuberi AR, Baker MC, Parsons TM, Castanedes-Casey M, Phillips V, Librero AL, Kurti A, Fryer JD, Bu G, Lutz C, Dickson DW, Rademakers R. Loss of Tmem106b exacerbates FTLD pathologies and causes motor deficits in progranulin-deficient mice. EMBO Rep. 2020 Oct 5;21(10):e50197. Epub 2020 Aug 5 PubMed.

    Feng T, Mai S, Roscoe JM, Sheng RR, Ullah M, Zhang J, Katz II, Yu H, Xiong W, Hu F. Loss of TMEM106B and PGRN leads to severe lysosomal abnormalities and neurodegeneration in mice. EMBO Rep. 2020 Oct 5;21(10):e50219. Epub 2020 Aug 10 PubMed.

    Feng T, Sheng RR, Solé-Domènech S, Ullah M, Zhou X, Mendoza CS, Enriquez LC, Katz II, Paushter DH, Sullivan PM, Wu X, Maxfield FR, Hu F. A role of the frontotemporal lobar degeneration risk factor TMEM106B in myelination. Brain. 2020 Jul 1;143(7):2255-2271. PubMed.

    Zhou X, Nicholson AM, Ren Y, Brooks M, Jiang P, Zuberi A, Phuoc HN, Perkerson RB, Matchett B, Parsons TM, Finch NA, Lin W, Qiao W, Castanedes-Casey M, Phillips V, Librero AL, Asmann Y, Bu G, Murray ME, Lutz C, Dickson DW, Rademakers R. Loss of TMEM106B leads to myelination deficits: implications for frontotemporal dementia treatment strategies. Brain. 2020 Jun 1;143(6):1905-1919. PubMed.

    Lee JY, Harney DJ, Teo JD, Kwok JB, Sutherland GT, Larance M, Don AS. The major TMEM106B dementia risk allele affects TMEM106B protein levels, fibril formation, and myelin lipid homeostasis in the ageing human hippocampus. Mol Neurodegener. 2023 Sep 19;18(1):63. PubMed. Correction.

    View all comments by Markus Damme

  2. Previous work, though highlighting the association of TMEM106B with multiple pathologies, has not shed light on the mechanisms of TMEM106B function. Here, the manuscript by Takahashi et al. reports lipid dysregulation in TMEM106B-deficient mouse brain tissue. In addition to reduction in the galactosylceramide (GalCer) and sulfatide levels, the authors elegantly show direct interaction between TMEM106B and galactosylceramidase (GALC), a hydrolyzing enzyme of GalCer. The authors also show increased GALC activity consistent with the loss of GalCer in brain tissue from TMEM106B deficient mice.

    Other lipids t affected by TMEM106B deficiency included the phospholipids phosphatidic acid (PA), phosphatidylcholine (PC), and phosphatidylethanolamine (PE). It will be necessary to determine if metabolic enzymes for these lipids are also regulated by TMEM106B, or if they are further downstream of GalCer and sulfatide metabolism. It would also be important to determine if acyl chain content and phospholipid saturation state are altered in the TMEM106B deficient brains.

    Though TMEM106b mutations T185S and D252N have been associated with frontotemporal lobar dementia (FTLD) and hypomyelination leukodystrophy (HLD), respectively, there is no change in binding of these mutants to GALC. It will be critical to determine if TMEM106B has a function independent of GALC regulation, which is disrupted by the mutations. Further, it is not known if the fibrilization of the c-term of GALC is associated with changes in GALC activity.

    The mechanisms underlying the regulation of the GALC activity by TMEM106B remain unclear. In addition to GALC activity in brain region homogenates, it would be important to use a purified GALC enzyme activity assay reconstituted with TMEM106B to determine if effects on activity are direct or indirect.

    Further studies are necessary to fully understand the activity of TMEM106B and how it regulates GalCer and sulfatide levels, but also how it leads to major changes in other lipid classes, including phospholipid species such as PA, PC and PE.

    View all comments by Laura Beth McIntire

  3. Since the discovery linking TMEM106B variants to progranulin deficient forms of frontotemporal dementia (Van Deerlin et al., 2010), the therapeutic value of modulating TMEM106B has been intensely researched (Werner et al., 2020; Feng et al., 2020; Zhou et al., 2020; Klein et al., 2017). Throughout these datasets, Tmem106b deficiency alone appears to cause mild phenotypes. The data in this new manuscript from Takahashi et al. extends this perspective, showing a mild lipid-related phenotype in the mouse brain and building on lipid phenotypes described in mice carrying Grn deficiency, as well as other models of more common neurodegenerative diseases (Boland et al., 2022; Brekk et al., 2020; Hallett et al, 2019; Hallett et al., 2018; Takahashi et al., 2023). Clearly, experimental data continues to link lipid regulation and inflammation to brain health. New thinking is now needed to test approaches that reestablish lipid homeostasis, supporting the health of vulnerable brain regions.

    References:

    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.

    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.

    Feng T, Mai S, Roscoe JM, Sheng RR, Ullah M, Zhang J, Katz II, Yu H, Xiong W, Hu F. Loss of TMEM106B and PGRN leads to severe lysosomal abnormalities and neurodegeneration in mice. EMBO Rep. 2020 Oct 5;21(10):e50219. Epub 2020 Aug 10 PubMed.

    Zhou X, Brooks M, Jiang P, Koga S, Zuberi AR, Baker MC, Parsons TM, Castanedes-Casey M, Phillips V, Librero AL, Kurti A, Fryer JD, Bu G, Lutz C, Dickson DW, Rademakers R. Loss of Tmem106b exacerbates FTLD pathologies and causes motor deficits in progranulin-deficient mice. EMBO Rep. 2020 Oct 5;21(10):e50197. Epub 2020 Aug 5 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.

    Boland S, Swarup S, Ambaw YA, Malia PC, Richards RC, Fischer AW, Singh S, Aggarwal G, Spina S, Nana AL, Grinberg LT, Seeley WW, Surma MA, Klose C, Paulo JA, Nguyen AD, Harper JW, Walther TC, Farese RV Jr. Deficiency of the frontotemporal dementia gene GRN results in gangliosidosis. Nat Commun. 2022 Oct 7;13(1):5924. PubMed.

    Brekk OR, Honey JR, Lee S, Hallett PJ, Isacson O. Cell type-specific lipid storage changes in Parkinson's disease patient brains are recapitulated by experimental glycolipid disturbance. Proc Natl Acad Sci U S A. 2020 Nov 3;117(44):27646-27654. Epub 2020 Oct 15 PubMed.

    Hallett PJ, Engelender S, Isacson O. Lipid and immune abnormalities causing age-dependent neurodegeneration and Parkinson's disease. J Neuroinflammation. 2019 Jul 22;16(1):153. PubMed.

    Hallett PJ, Huebecker M, Brekk OR, Moloney EB, Rocha EM, Priestman DA, Platt FM, Isacson O. Glycosphingolipid levels and glucocerebrosidase activity are altered in normal aging of the mouse brain. Neurobiol Aging. 2018 Jul;67:189-200. Epub 2018 Mar 29 PubMed.

    Takahashi H, Perez-Canamas A, Ye H, Han X, Strittmatter SM. Lysosomal TMEM106B interacts with galactosylceramidase to regulate myelin lipid metabolism. bioRxiv. 2023 Sep 14; PubMed.

    View all comments by Oliver Cooper View all comments by Ole Isacson
    • User Profile Image Anja Capell
      DZNE-German Center for Neurodegenerative Disease
    • Posted:

    It is timely to investigate the function of the lysosomal type II transmembrane protein TMEM106B, as the Strittmatter lab have done here. Emerging evidence suggests TMEM106B is a key protein in aging and neuronal health, and it is also associated with several neurodegenerative diseases. Initially, TMEM106B was detected as a progranulin-associated risk factor in frontotemporal dementia. As recently reported, aging and neurodegeneration seem to be accompanied by luminal formation of TMEM106B amyloid fibrils. Now, this work by Takahashi and colleagues suggests that TMEM106B regulates myelin lipid metabolism by modulating galactocerebrosidase. Impaired myelination in TMEM106B knockout mice has already been reported. Here, Takahashi et al. show that TMEM106B deficiency results in enhanced galactocerebrosidase activity, which leads to reduced levels of the substrates galactosylceramide and sulfatide, with the consequence of impaired myelination.

    However, for Krabbe disease, a globoid cell leukodystrophy, the opposite has been shown: Reduced galactocerebrosidase activity results in demyelination of the CNS and peripheral nervous system. Furthermore, the hydrolysis of galactosylceramide in vivo requires a noncatalytic small subunit of prosaposin: saposin A. It would be interesting to know if saposin A levels are also reduced upon TMEM106B deficiency. Here, prosaposin, or saposin A, could provide a link to progranulin, since according to the data from the Strittmatter lab, progranulin and TMEM106B are not players of the same lipid metabolic pathways.

    Thus, more work would be required to shed light on the lipid dysregulation caused by progranulin and/or TMEM106B deficiency and to find out if lipid dysregulation is causative for the devastating phenotype seen in progranulin and TMEM106B double knockout mice.

    View all comments by Anja Capell

Make a Comment

To make a comment you must login or register.

References

News Citations

  1. Surprise! TMEM106b Fibrils Found in Neurodegenerative Diseases
  2. Massive GWAS Meta-Analysis Digs Up Trove of Alzheimer’s Genes
  3. From a Million Samples, GWAS Squeezes Out Seven New Alzheimer's Spots
  4. Lysosomes Take Center Stage in Parkinson’s and Frontotemporal Dementia
  5. Nixing TMEM106b Fans the Flames of Progranulin Deficiency
  6. TMEM106B and Progranulin Duke It Out at the Lysosome

Paper Citations

  1. 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.
  2. Perez-Canamas A, Takahashi H, Lindborg JA, Strittmatter SM. Fronto-temporal dementia risk gene TMEM106B has opposing effects in different lysosomal storage disorders. Brain Commun. 2021;3(1):fcaa200. Epub 2020 Nov 16 PubMed.
  3. Boland S, Swarup S, Ambaw YA, Malia PC, Richards RC, Fischer AW, Singh S, Aggarwal G, Spina S, Nana AL, Grinberg LT, Seeley WW, Surma MA, Klose C, Paulo JA, Nguyen AD, Harper JW, Walther TC, Farese RV Jr. Deficiency of the frontotemporal dementia gene GRN results in gangliosidosis. Nat Commun. 2022 Oct 7;13(1):5924. PubMed.
  4. 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.
  5. Boggs JM. Role of galactosylceramide and sulfatide in oligodendrocytes and CNS myelin: formation of a glycosynapse. Adv Neurobiol. 2014;9:263-91. PubMed.
  6. Grassi S, Prioni S, Cabitta L, Aureli M, Sonnino S, Prinetti A. The Role of 3-O-Sulfogalactosylceramide, Sulfatide, in the Lateral Organization of Myelin Membrane. Neurochem Res. 2016 Feb;41(1-2):130-43. Epub 2015 Nov 5 PubMed.
  7. Kister A, Kister I. Overview of myelin, major myelin lipids, and myelin-associated proteins. Front Chem. 2022;10:1041961. Epub 2023 Feb 21 PubMed.
  8. Bartzokis G, Cummings JL, Sultzer D, Henderson VW, Nuechterlein KH, Mintz J. White matter structural integrity in healthy aging adults and patients with Alzheimer disease: a magnetic resonance imaging study. Arch Neurol. 2003 Mar;60(3):393-8. PubMed.
  9. Marian OC, Teo JD, Lee JY, Song H, Kwok JB, Landin-Romero R, Halliday G, Don AS. Disrupted myelin lipid metabolism differentiates frontotemporal dementia caused by GRN and C9orf72 gene mutations. Acta Neuropathol Commun. 2023 Mar 27;11(1):52. PubMed.
  10. Lee JY, Harney DJ, Teo JD, Kwok JB, Sutherland GT, Larance M, Don AS. The major TMEM106B dementia risk allele affects TMEM106B protein levels, fibril formation, and myelin lipid homeostasis in the ageing human hippocampus. Mol Neurodegener. 2023 Sep 19;18(1):63. PubMed. Correction.

Further Reading

Primary Papers

  1. Takahashi H, Perez-Canams A, Ye H, Han X, Strittmatter SM. Lysosomal TMEM106B interacts with galactosylceramidase to regulate myelin lipid metabolism. 2023 Sep 14 10.1101/2023.09.14.557804 (version 1) bioRxiv.

Annotate

To make an annotation you must Login or Register.