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.
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.
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.
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.
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.
Comments
University of Kiel
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 DammeWeill Cornell
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 McIntireHarvard Medical School
Harvard Medical School
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 Ole IsacsonDZNE-German Center for Neurodegenerative Disease
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.
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