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Open Access 01-12-2023 | Frontotemporal Dementia | Research

Disrupted myelin lipid metabolism differentiates frontotemporal dementia caused by GRN and C9orf72 gene mutations

Authors: Oana C. Marian, Jonathan D. Teo, Jun Yup Lee, Huitong Song, John B. Kwok, Ramon Landin-Romero, Glenda Halliday, Anthony S. Don

Published in: Acta Neuropathologica Communications | Issue 1/2023

Abstract

Heterozygous mutations in the GRN gene and hexanucleotide repeat expansions in C9orf72 are the two most common genetic causes of Frontotemporal Dementia (FTD) with TDP-43 protein inclusions. The triggers for neurodegeneration in FTD with GRN (FTD-GRN) or C9orf72 (FTD-C9orf72) gene abnormalities are unknown, although evidence from mouse and cell culture models suggests that GRN mutations disrupt lysosomal lipid catabolism. To determine how brain lipid metabolism is affected in familial FTD with TDP-43 inclusions, and how this is related to myelin and lysosomal markers, we undertook comprehensive lipidomic analysis, enzyme activity assays, and western blotting on grey and white matter samples from the heavily-affected frontal lobe and less-affected parietal lobe of FTD-GRN cases, FTD-C9orf72 cases, and age-matched neurologically-normal controls. Substantial loss of myelin-enriched sphingolipids (sulfatide, galactosylceramide, sphingomyelin) and myelin proteins was observed in frontal white matter of FTD-GRN cases. A less-pronounced, yet statistically significant, loss of sphingolipids was also observed in FTD-C9orf72. FTD-GRN was distinguished from FTD-C9orf72 and control cases by increased acylcarnitines in frontal grey matter and marked accumulation of cholesterol esters in both frontal and parietal white matter, indicative of myelin break-down. Both FTD-GRN and FTD-C9orf72 cases showed significantly increased lysosomal and phagocytic protein markers, however galactocerebrosidase activity, required for lysosomal catabolism of galactosylceramide and sulfatide, was selectively increased in FTD-GRN. We conclude that both C9orf72 and GRN mutations are associated with disrupted lysosomal homeostasis and white matter lipid loss, but GRN mutations cause a more pronounced disruption to myelin lipid metabolism. Our findings support the hypothesis that hyperactive myelin lipid catabolism is a driver of gliosis and neurodegeneration in FTD-GRN. Since FTD-GRN is associated with white matter hyperintensities by MRI, our data provides important biochemical evidence supporting the use of MRI measures of white matter integrity in the diagnosis and management of FTD.

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Olney NT, Spina S, Miller BL (2017) Frontotemporal Dementia. Neurologic clinics 35:339 – 74. https://doi.org/10.1016/j.ncl.2017.01.008

Hodges JR, Davies R, Xuereb J, Kril J, Halliday G (2003) Survival in frontotemporal dementia. Neurology 61:349–354. https://doi.org/10.1212/01.Wnl.0000078928.20107.52CrossRefPubMed

Greaves CV, Rohrer JD (2019) An update on genetic frontotemporal dementia. J Neurol 266:2075–2086. https://doi.org/10.1007/s00415-019-09363-4CrossRefPubMedPubMedCentral

Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman H, Feiden W, Kretzschmar HA, Trojanowski JQ, Lee VM (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133. https://doi.org/10.1126/science.1134108CrossRefPubMed

Cruts M, Gijselinck I, van der Zee J, Engelborghs S, Wils H, Pirici D, Rademakers R, Vandenberghe R, Dermaut B, Martin JJ, van Duijn C, Peeters K, Sciot R, Santens P, De Pooter T, Mattheijssens M, Van den Broeck M, Cuijt I, Vennekens K, De Deyn PP, Kumar-Singh S, Van Broeckhoven C (2006) Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 442:920–924. https://doi.org/10.1038/nature05017CrossRefPubMed

Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C, Snowden J, Adamson J, Sadovnick AD, Rollinson S, Cannon A, Dwosh E, Neary D, Melquist S, Richardson A, Dickson D, Berger Z, Eriksen J, Robinson T, Zehr C, Dickey CA, Crook R, McGowan E, Mann D, Boeve B, Feldman H, Hutton M (2006) Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442:916–919. https://doi.org/10.1038/nature05016CrossRefPubMed

Majounie E, Renton AE, Mok K, Dopper EGP, Waite A, Rollinson S, Chiò A, Restagno G, Nicolaou N, Simon-Sanchez J, van Swieten JC, Abramzon Y, Johnson JO, Sendtner M, Pamphlett R, Orrell RW, Mead S, Sidle KC, Houlden H, Rohrer JD, Morrison KE, Pall H, Talbot K, Ansorge O, Hernandez DG, Arepalli S, Sabatelli M, Mora G, Corbo M, Giannini F, Calvo A, Englund E, Borghero G, Floris GL, Remes AM, Laaksovirta H, McCluskey L, Trojanowski JQ, Van Deerlin VM, Schellenberg GD, Nalls MA, Drory VE, Lu C-S, Yeh T-H, Ishiura H, Takahashi Y, Tsuji S, Le Ber I, Brice A, Drepper C, Williams N, Kirby J, Shaw P, Hardy J, Tienari PJ, Heutink P, Morris HR, Pickering-Brown S, Traynor BJ (2012) Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol 11:323–330CrossRefPubMedPubMedCentral

DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, Nicholson AM, Finch NA, Flynn H, Adamson J, Kouri N, Wojtas A, Sengdy P, Hsiung G-YR, Karydas A, Seeley WW, Josephs KA, Coppola G, Geschwind DH, Wszolek ZK, Feldman H, Knopman DS, Petersen RC, Miller BL, Dickson DW, Boylan KB, Graff-Radford NR, Rademakers R (2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72:245–256. https://doi.org/10.1016/j.neuron.2011.09.011CrossRefPubMedPubMedCentral

Hu F, Padukkavidana T, Vaegter CB, Brady OA, Zheng Y, Mackenzie IR, Feldman HH, Nykjaer A, Strittmatter SM (2010) Sortilin-mediated endocytosis determines levels of the frontotemporal dementia protein, progranulin. Neuron 68:654–667. https://doi.org/10.1016/j.neuron.2010.09.034CrossRefPubMedPubMedCentral

10.

Zhou X, Sun L, Bracko O, Choi JW, Jia Y, Nana AL, Brady OA, Hernandez JCC, Nishimura N, Seeley WW, Hu F (2017) Impaired prosaposin lysosomal trafficking in frontotemporal lobar degeneration due to progranulin mutations. Nat Commun 8:15277. https://doi.org/10.1038/ncomms15277CrossRefPubMedPubMedCentral

11.

Smith KR, Damiano J, Franceschetti S, Carpenter S, Canafoglia L, Morbin M, Rossi G, Pareyson D, Mole SE, Staropoli JF, Sims KB, Lewis J, Lin WL, Dickson DW, Dahl HH, Bahlo M, Berkovic SF (2012) Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage. Am J Hum Genet 90:1102–1107. https://doi.org/10.1016/j.ajhg.2012.04.021CrossRefPubMedPubMedCentral

12.

Almeida MR, Macário MC, Ramos L, Baldeiras I, Ribeiro MH, Santana I (2016) Portuguese family with the co-occurrence of frontotemporal lobar degeneration and neuronal ceroid lipofuscinosis phenotypes due to progranulin gene mutation. Neurobiology of Aging 41:200.e1-00.e5

13.

Gotzl JK, Mori K, Damme M, Fellerer K, Tahirovic S, Kleinberger G, Janssens J, van der Zee J, Lang CM, Kremmer E, Martin JJ, Engelborghs S, Kretzschmar HA, Arzberger T, Van Broeckhoven C, Haass C, Capell A (2014) Common pathobiochemical hallmarks of progranulin-associated frontotemporal lobar degeneration and neuronal ceroid lipofuscinosis. Acta Neuropathol 127:845–860. https://doi.org/10.1007/s00401-014-1262-6CrossRefPubMed

14.

Ahmed Z, Sheng H, Xu YF, Lin WL, Innes AE, Gass J, Yu X, Wuertzer CA, Hou H, Chiba S, Yamanouchi K, Leissring M, Petrucelli L, Nishihara M, Hutton ML, McGowan E, Dickson DW, Lewis J (2010) Accelerated lipofuscinosis and ubiquitination in granulin knockout mice suggest a role for progranulin in successful aging. Am J Pathol 177:311–324. https://doi.org/10.2353/ajpath.2010.090915CrossRefPubMedPubMedCentral

15.

Ward ME, Chen R, Huang HY, Ludwig C, Telpoukhovskaia M, Taubes A, Boudin H, Minami SS, Reichert M, Albrecht P, Gelfand JM, Cruz-Herranz A, Cordano C, Alavi MV, Leslie S, Seeley WW, Miller BL, Bigio E, Mesulam MM, Bogyo MS, Mackenzie IR, Staropoli JF, Cotman SL, Huang EJ, Gan L, Green AJ (2017) Individuals with progranulin haploinsufficiency exhibit features of neuronal ceroid lipofuscinosis. Sci Transl Med 9. https://doi.org/10.1126/scitranslmed.aah5642

16.

Evers BM, Rodriguez-Navas C, Tesla RJ, Prange-Kiel J, Wasser CR, Yoo KS, McDonald J, Cenik B, Ravenscroft TA, Plattner F, Rademakers R, Yu G, White CL 3rd, Herz J (2017) Lipidomic and transcriptomic basis of lysosomal dysfunction in Progranulin Deficiency. Cell Rep 20:2565–2574. https://doi.org/10.1016/j.celrep.2017.08.056

17.

Tanaka Y, Suzuki G, Matsuwaki T, Hosokawa M, Serrano G, Beach TG, Yamanouchi K, Hasegawa M, Nishihara M (2017) Progranulin regulates lysosomal function and biogenesis through acidification of lysosomes. Hum Mol Genet 26:969–988. https://doi.org/10.1093/hmg/ddx011CrossRefPubMed

18.

Valdez C, Ysselstein D, Young TJ, Zheng J, Krainc D (2020) Progranulin mutations result in impaired processing of prosaposin and reduced glucocerebrosidase activity. Hum Mol Genet 29:716–726. https://doi.org/10.1093/hmg/ddz229CrossRefPubMed

19.

Logan T, Simon MJ, Rana A, Cherf GM, Srivastava A, Davis SS, Low RLY, Chiu CL, Fang M, Huang F, Bhalla A, Llapashtica C, Prorok R, Pizzo ME, Calvert MEK, Sun EW, Hsiao-Nakamoto J, Rajendra Y, Lexa KW, Srivastava DB, van Lengerich B, Wang J, Robles-Colmenares Y, Kim DJ, Duque J, Lenser M, Earr TK, Nguyen H, Chau R, Tsogtbaatar B, Ravi R, Skuja LL, Solanoy H, Rosen HJ, Boeve BF, Boxer AL, Heuer HW, Dennis MS, Kariolis MS, Monroe KM, Przybyla L, Sanchez PE, Meisner R, Diaz D, Henne KR, Watts RJ, Henry AG, Gunasekaran K, Astarita G, Suh JH, Lewcock JW, DeVos SL, Di Paolo G (2021) Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic. Cell 184:4651-68 e25. https://doi.org/10.1016/j.cell.2021.08.002

20.

Mori K, Weng SM, Arzberger T, May S, Rentzsch K, Kremmer E, Schmid B, Kretzschmar HA, Cruts M, Van Broeckhoven C, Haass C, Edbauer D (2013) The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 339:1335-8. https://doi.org/10.1126/science.1232927

21.

Gendron TF, Bieniek KF, Zhang YJ, Jansen-West K, Ash PE, Caulfield T, Daughrity L, Dunmore JH, Castanedes-Casey M, Chew J, Cosio DM, van Blitterswijk M, Lee WC, Rademakers R, Boylan KB, Dickson DW, Petrucelli L (2013) Antisense transcripts of the expanded C9ORF72 hexanucleotide repeat form nuclear RNA foci and undergo repeat-associated non-ATG translation in c9FTD/ALS. Acta Neuropathol 126:829–844. https://doi.org/10.1007/s00401-013-1192-8CrossRefPubMedPubMedCentral

22.

Kwon I, Xiang S, Kato M, Wu L, Theodoropoulos P, Wang T, Kim J, Yun J, Xie Y, McKnight SL (2014) Poly-dipeptides encoded by the C9orf72 repeats bind nucleoli, impede RNA biogenesis, and kill cells. Science 345:1139–1145. https://doi.org/10.1126/science.1254917CrossRefPubMedPubMedCentral

23.

Shi Y, Lin S, Staats KA, Li Y, Chang WH, Hung ST, Hendricks E, Linares GR, Wang Y, Son EY, Wen X, Kisler K, Wilkinson B, Menendez L, Sugawara T, Woolwine P, Huang M, Cowan MJ, Ge B, Koutsodendris N, Sandor KP, Komberg J, Vangoor VR, Senthilkumar K, Hennes V, Seah C, Nelson AR, Cheng TY, Lee SJ, August PR, Chen JA, Wisniewski N, Hanson-Smith V, Belgard TG, Zhang A, Coba M, Grunseich C, Ward ME, van den Berg LH, Pasterkamp RJ, Trotti D, Zlokovic BV, Ichida JK (2018) Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons. Nat Med 24:313–325. https://doi.org/10.1038/nm.4490CrossRefPubMedPubMedCentral

24.

Farg MA, Sundaramoorthy V, Sultana JM, Yang S, Atkinson RAK, Levina V, Halloran MA, Gleeson PA, Blair IP, Soo KY, King AE, Atkin JD (2014) C9ORF72, implicated in amytrophic lateral sclerosis and frontotemporal dementia, regulates endosomal trafficking. Hum Mol Genet 23:3579–3595. https://doi.org/10.1093/hmg/ddu068CrossRefPubMedPubMedCentral

25.

Sudre CH, Bocchetta M, Cash D, Thomas DL, Woollacott I, Dick KM, van Swieten J, Borroni B, Galimberti D, Masellis M, Tartaglia MC, Rowe JB, Graff C, Tagliavini F, Frisoni G, Laforce R Jr, Finger E, de Mendonca A, Sorbi S, Ourselin S, Cardoso MJ, Rohrer JD (2017) Genetic Ftd Initiative G White matter hyperintensities are seen only in GRN mutation carriers in the GENFI cohort. Neuroimage Clin 15:171 – 80. https://doi.org/10.1016/j.nicl.2017.04.015

26.

Paternico D, Premi E, Gazzina S, Cosseddu M, Alberici A, Archetti S, Cotelli MS, Micheli A, Turla M, Gasparotti R, Padovani A, Borroni B (2016) White matter hyperintensities characterize monogenic frontotemporal dementia with granulin mutations. Neurobiol Aging 38:176–180. https://doi.org/10.1016/j.neurobiolaging.2015.11.011CrossRefPubMed

27.

Ameur F, Colliot O, Caroppo P, Stroer S, Dormont D, Brice A, Azuar C, Dubois B, Le Ber I, Bertrand A (2016) White matter lesions in FTLD: distinct phenotypes characterize GRN and C9ORF72 mutations. Neurol Genet 2:e47. https://doi.org/10.1212/NXG.0000000000000047CrossRefPubMedPubMedCentral

28.

Jiskoot LC, Bocchetta M, Nicholas JM, Cash DM, Thomas D, Modat M, Ourselin S, Rombouts S, Dopper EGP, Meeter LH, Panman JL, van Minkelen R, van der Ende EL, Donker Kaat L, Pijnenburg YAL, Borroni B, Galimberti D, Masellis M, Tartaglia MC, Rowe J, Graff C, Tagliavini F, Frisoni GB, Laforce R Jr, Finger E, de Mendonca A, Sorbi S, Genetic Frontotemporal dementia I, Papma JM, van Swieten JC, Rohrer JD (2018) Presymptomatic white matter integrity loss in familial frontotemporal dementia in the GENFI cohort: A cross-sectional diffusion tensor imaging study. Ann Clin Transl Neurol 5:1025-36. https://doi.org/10.1002/acn3.601

29.

Mahoney CJ, Simpson IJ, Nicholas JM, Fletcher PD, Downey LE, Golden HL, Clark CN, Schmitz N, Rohrer JD, Schott JM, Zhang H, Ourselin S, Warren JD, Fox NC (2015) Longitudinal diffusion tensor imaging in frontotemporal dementia. Ann Neurol 77:33–46. https://doi.org/10.1002/ana.24296CrossRefPubMed

30.

Quarles RH, Macklin WB, Morell P (2006) Myelin formation, structure and Biochemistry. In: Brady ST et al (eds) Basic Neurochemistry: Molecular, Cellular and Medical Aspects. Elsevier, pp 51–71

31.

Couttas TA, Rustam YH, Song H, Qi Y, Teo JD, Chen J, Reid GE, Don AS (2020) A Novel Function of Sphingosine Kinase 2 in the Metabolism of Sphinga-4,14-Diene Lipids. Metabolites 10. https://doi.org/10.3390/metabo10060236

32.

Oftedal L, Maple-Grødem J, Førland MGG, Alves G, Lange J (2020) Validation and assessment of preanalytical factors of a fluorometric in vitro assay for glucocerebrosidase activity in human cerebrospinal fluid. Sci Rep 10:22098. https://doi.org/10.1038/s41598-020-79104-5CrossRefPubMedPubMedCentral

33.

Song H, McEwen HP, Duncan T, Lee JY, Teo JD, Don AS (2021) Sphingosine kinase 2 is essential for remyelination following cuprizone intoxication. Glia 69:2863–2881. https://doi.org/10.1002/glia.24074CrossRefPubMed

34.

Bankhead P, Loughrey MB, Fernández JA, Dombrowski Y, McArt DG, Dunne PD, McQuaid S, Gray RT, Murray LJ, Coleman HG, James JA, Salto-Tellez M, Hamilton PW (2017) QuPath: open source software for digital pathology image analysis. Sci Rep 7:16878. https://doi.org/10.1038/s41598-017-17204-5CrossRefPubMedPubMedCentral

35.

Mackenzie IR, Neumann M, Baborie A, Sampathu DM, Du Plessis D, Jaros E, Perry RH, Trojanowski JQ, Mann DM, Lee VM (2011) A harmonized classification system for FTLD-TDP pathology. Acta Neuropathol 122:111–113. https://doi.org/10.1007/s00401-011-0845-8CrossRefPubMedPubMedCentral

36.

Kril JJ, Halliday GM (2004) Clinicopathological staging of frontotemporal dementia severity: correlation with regional atrophy. Dement Geriatr Cogn Disord 17:311–315. https://doi.org/10.1159/000077161CrossRefPubMed

37.

Manera AL, Dadar M, Collins DL, Ducharme S, Frontotemporal Lobar Degeneration Neuroimaging I (2019) Deformation based morphometry study of longitudinal MRI changes in behavioral variant frontotemporal dementia. NeuroImage Clin 24:102079–102079. https://doi.org/10.1016/j.nicl.2019.102079CrossRefPubMedPubMedCentral

38.

Vanier MT, Svennerholm L (1975) Chemical pathology of Krabbe’s disease. III. Ceramide-hexosides and gangliosides of brain. Acta Paediatr Scand 64:641–648CrossRefPubMed

39.

Madhavarao CN, Moffett JR, Moore RA, Viola RE, Namboodiri MA, Jacobowitz DM (2004) Immunohistochemical localization of aspartoacylase in the rat central nervous system. J Comp Neurol 472:318–329. https://doi.org/10.1002/cne.20080CrossRefPubMed

40.

Nugent AA, Lin K, van Lengerich B, Lianoglou S, Przybyla L, Davis SS, Llapashtica C, Wang J, Kim DJ, Xia D, Lucas A, Baskaran S, Haddick PCG, Lenser M, Earr TK, Shi J, Dugas JC, Andreone BJ, Logan T, Solanoy HO, Chen H, Srivastava A, Poda SB, Sanchez PE, Watts RJ, Sandmann T, Astarita G, Lewcock JW, Monroe KM, Di Paolo G (2020) TREM2 regulates microglial cholesterol metabolism upon chronic phagocytic challenge. Neuron 105:837 – 54 e9. https://doi.org/10.1016/j.neuron.2019.12.007

41.

Cantuti-Castelvetri L, Fitzner D, Bosch-Queralt M, Weil MT, Su M, Sen P, Ruhwedel T, Mitkovski M, Trendelenburg G, Lutjohann D, Mobius W, Simons M (2018) Defective cholesterol clearance limits remyelination in the aged central nervous system. Science 359:684–688. https://doi.org/10.1126/science.aan4183CrossRefPubMed

42.

Schmitt S, Castelvetri LC, Simons M (2015) Metabolism and functions of lipids in myelin. Biochim Biophys Acta 1851:999–1005. https://doi.org/10.1016/j.bbalip.2014.12.016CrossRefPubMed

43.

Zhou X, Paushter DH, Pagan MD, Kim D, Nunez Santos M, Lieberman RL, Overkleeft HS, Sun Y, Smolka MB, Hu F (2019) Progranulin deficiency leads to reduced glucocerebrosidase activity. PLoS ONE 14:e0212382. https://doi.org/10.1371/journal.pone.0212382CrossRefPubMedPubMedCentral

44.

Arrant AE, Roth JR, Boyle NR, Kashyap SN, Hoffmann MQ, Murchison CF, Ramos EM, Nana AL, Spina S, Grinberg LT, Miller BL, Seeley WW, Roberson ED (2019) Impaired ß-glucocerebrosidase activity and processing in frontotemporal dementia due to progranulin mutations. Acta Neuropathol Commun 7:218. https://doi.org/10.1186/s40478-019-0872-6CrossRefPubMedPubMedCentral

45.

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 (2022) Deficiency of the frontotemporal dementia gene GRN results in gangliosidosis. Nat Commun 13:5924. https://doi.org/10.1038/s41467-022-33500-9CrossRefPubMedPubMedCentral

46.

Wang Y, Cella M, Mallinson K, Ulrich JD, Young KL, Robinette ML, Gilfillan S, Krishnan GM, Sudhakar S, Zinselmeyer BH, Holtzman DM, Cirrito JR, Colonna M (2015) TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model. Cell 160:1061–1071. https://doi.org/10.1016/j.cell.2015.01.049CrossRefPubMedPubMedCentral

47.

Woollacott IOC, Bocchetta M, Sudre CH, Ridha BH, Strand C, Courtney R, Ourselin S, Cardoso MJ, Warren JD, Rossor MN, Revesz T, Fox NC, Holton JL, Lashley T, Rohrer JD (2018) Pathological correlates of white matter hyperintensities in a case of progranulin mutation associated frontotemporal dementia. Neurocase 24:166–174. https://doi.org/10.1080/13554794.2018.1506039CrossRefPubMedPubMedCentral

48.

Sirisi S, Querol-Vilaseca M, Dols-Icardo O, Pegueroles J, Montal V, Munoz L, Torres S, Ferrer-Raventos P, Iulita MF, Sanchez-Aced E, Blesa R, Illan-Gala I, Molina-Porcel L, Borrego-Ecija S, Sanchez-Valle R, Clarimon J, Belbin O, Fortea J, Lleo A (2022) Myelin loss in C9orf72 hexanucleotide expansion carriers. J Neurosci Res 100:1862–1875. https://doi.org/10.1002/jnr.25100CrossRefPubMed

49.

Wender M, Filipek-Wender H, Stanislawska J (1974) Cholesteryl esters of the brain in demyelinating diseases. Clin Chim Acta 54:269–275. https://doi.org/10.1016/0009-8981(74)90245-9CrossRefPubMed

50.

Theda C, Moser AB, Powers JM, Moser HW (1992) Phospholipids in X-linked adrenoleukodystrophy white matter: fatty acid abnormalities before the onset of demyelination. J Neurol Sci 110:195–204. https://doi.org/10.1016/0022-510x(92)90028-jCrossRefPubMed

51.

Chiang JYL, Ferrell JM (2020) Up to date on cholesterol 7 alpha-hydroxylase (CYP7A1) in bile acid synthesis. Liver Res 4:47–63. https://doi.org/10.1016/j.livres.2020.05.001CrossRefPubMedPubMedCentral

52.

Cantoni C, Bollman B, Licastro D, Xie M, Mikesell R, Schmidt R, Yuede CM, Galimberti D, Olivecrona G, Klein RS, Cross AH, Otero K, Piccio L (2015) TREM2 regulates microglial cell activation in response to demyelination in vivo. Acta Neuropathol 129:429–447. https://doi.org/10.1007/s00401-015-1388-1CrossRefPubMedPubMedCentral

53.

Wu Y, Shao W, Todd TW, Tong J, Yue M, Koga S, Castanedes-Casey M, Librero AL, Lee CW, Mackenzie IR, Dickson DW, Zhang YJ, Petrucelli L, Prudencio M (2021) Microglial lysosome dysfunction contributes to white matter pathology and TDP-43 proteinopathy in GRN-associated FTD. Cell Rep 36:109581. https://doi.org/10.1016/j.celrep.2021.109581CrossRefPubMedPubMedCentral

54.

van der Kant R, Langness VF, Herrera CM, Williams DA, Fong LK, Leestemaker Y, Steenvoorden E, Rynearson KD, Brouwers JF, Helms JB, Ovaa H, Giera M, Wagner SL, Bang AG, Goldstein LSB (2019) Cholesterol Metabolism Is a Druggable Axis that Independently Regulates Tau and Amyloid-beta in iPSC-Derived Alzheimer’s Disease Neurons. Cell Stem Cell 24:363 – 75 e9. https://doi.org/10.1016/j.stem.2018.12.013

55.

Puglielli L, Konopka G, Pack-Chung E, Ingano LA, Berezovska O, Hyman BT, Chang TY, Tanzi RE, Kovacs DM (2001) Acyl-coenzyme A: cholesterol acyltransferase modulates the generation of the amyloid beta-peptide. Nat Cell Biol 3:905–912. https://doi.org/10.1038/ncb1001-905CrossRefPubMed

56.

Rinaldo P, Matern D, Bennett MJ (2002) Fatty acid Oxidation Disorders. Annu Rev Physiol 64:477–502. https://doi.org/10.1146/annurev.physiol.64.082201.154705CrossRefPubMed

57.

Jacova C, Hsiung G-YR, Tawankanjanachot I, Dinelle K, McCormick S, Gonzalez M, Lee H, Sengdy P, Bouchard-Kerr P, Baker M, Rademakers R, Sossi V, Stoessl AJ, Feldman HH, Mackenzie IR (2013) Anterior brain glucose hypometabolism predates dementia in progranulin mutation carriers. Neurology 81:1322–1331. https://doi.org/10.1212/WNL.0b013e3182a8237eCrossRefPubMedPubMedCentral

58.

Turk BR, Theda C, Fatemi A, Moser AB (2020) X-linked adrenoleukodystrophy: Pathology, pathophysiology, diagnostic testing, newborn screening and therapies. Int J Dev neuroscience: official J Int Soc Dev Neurosci 80:52–72. https://doi.org/10.1002/jdn.10003CrossRef

59.

Viader A, Sasaki Y, Kim S, Strickland A, Workman Cayce S, Yang K, Gross Richard W, Milbrandt J (2013) Aberrant Schwann cell lipid metabolism linked to mitochondrial deficits leads to Axon Degeneration and Neuropathy. Neuron 77:886–898CrossRefPubMedPubMedCentral

60.

Gotzl JK, Brendel M, Werner G, Parhizkar S, Sebastian Monasor L, Kleinberger G, Colombo AV, Deussing M, Wagner M, Winkelmann J, Diehl-Schmid J, Levin J, Fellerer K, Reifschneider A, Bultmann S, Bartenstein P, Rominger A, Tahirovic S, Smith ST, Madore C, Butovsky O, Capell A, Haass C (2019) Opposite microglial activation stages upon loss of PGRN or TREM2 result in reduced cerebral glucose metabolism. EMBO Mol Med 11. https://doi.org/10.15252/emmm.201809711

61.

Lall D, Lorenzini I, Mota TA, Bell S, Mahan TE, Ulrich JD, Davtyan H, Rexach JE, Muhammad A, Shelest O, Landeros J, Vazquez M, Kim J, Ghaffari L, O’Rourke JG, Geschwind DH, Blurton-Jones M, Holtzman DM, Sattler R, Baloh RH (2021) C9orf72 deficiency promotes microglial-mediated synaptic loss in aging and amyloid accumulation. Neuron 109:2275-91 e8. https://doi.org/10.1016/j.neuron.2021.05.020

62.

Zhang J, Velmeshev D, Hashimoto K, Huang YH, Hofmann JW, Shi X, Chen J, Leidal AM, Dishart JG, Cahill MK, Kelley KW, Liddelow SA, Seeley WW, Miller BL, Walther TC, Farese RV Jr, Taylor JP, Ullian EM, Huang B, Debnath J, Wittmann T, Kriegstein AR, Huang EJ (2020) Neurotoxic microglia promote TDP-43 proteinopathy in progranulin deficiency. Nature 588:459–465. https://doi.org/10.1038/s41586-020-2709-7CrossRefPubMedPubMedCentral

63.

O’Rourke JG, Bogdanik L, Yanez A, Lall D, Wolf AJ, Muhammad AK, Ho R, Carmona S, Vit JP, Zarrow J, Kim KJ, Bell S, Harms MB, Miller TM, Dangler CA, Underhill DM, Goodridge HS, Lutz CM, Baloh RH (2016) C9orf72 is required for proper macrophage and microglial function in mice. Science 351:1324–1329. https://doi.org/10.1126/science.aaf1064CrossRefPubMedPubMedCentral

64.

Brettschneider J, Toledo JB, Van Deerlin VM, Elman L, McCluskey L, Lee VM, Trojanowski JQ (2012) Microglial activation correlates with disease progression and upper motor neuron clinical symptoms in amyotrophic lateral sclerosis. PLoS ONE 7:e39216. https://doi.org/10.1371/journal.pone.0039216CrossRefPubMedPubMedCentral

65.

Sadler GL, Lewis KN, Narayana VK, De Souza DP, Mason J, McLean C, Gonsalvez DG, Turner BJ, Barton SK (2022) Lipid Metabolism Is Dysregulated in the Motor Cortex White Matter in Amyotrophic Lateral Sclerosis. Metabolites 12. https://doi.org/10.3390/metabo12060554

66.

Don AS, Hsiao JH, Bleasel JM, Couttas TA, Halliday GM, Kim W (2014) Altered lipid levels provide evidence for myelin dysfunction in multiple system atrophy. Acta Neuropathol Commun 2:150. https://doi.org/10.1186/s40478-014-0150-6CrossRefPubMedPubMedCentral

67.

Xicoy H, Brouwers JF, Wieringa B, Martens GJM (2020) Explorative combined lipid and transcriptomic profiling of Substantia Nigra and Putamen in Parkinson’s Disease. Cells 9. https://doi.org/10.3390/cells9091966

68.

Wood PL, Tippireddy S, Feriante J, Woltjer RL (2018) Augmented frontal cortex diacylglycerol levels in Parkinson’s disease and Lewy Body Disease. PLoS ONE 13:e0191815. https://doi.org/10.1371/journal.pone.0191815CrossRefPubMedPubMedCentral

69.

Cheng D, Jenner AM, Shui G, Cheong WF, Mitchell TW, Nealon JR, Kim WS, McCann H, Wenk MR, Halliday GM, Garner B (2011) Lipid pathway alterations in Parkinson’s disease primary visual cortex. PLoS ONE 6:e17299. https://doi.org/10.1371/journal.pone.0017299CrossRefPubMedPubMedCentral

70.

Couttas TA, Kain N, Suchowerska AK, Quek LE, Turner N, Fath T, Garner B, Don AS (2016) Loss of ceramide synthase 2 activity, necessary for myelin biosynthesis, precedes tau pathology in the cortical pathogenesis of Alzheimer’s disease. Neurobiol Aging 43:89–100. https://doi.org/10.1016/j.neurobiolaging.2016.03.027CrossRefPubMed

71.

Huynh K, Piguet O, Kwok J, Dobson-Stone C, Halliday GM, Hodges JR, Landin-Romero R (2021) Clinical and biological Correlates of White Matter Hyperintensities in patients with behavioral-variant Frontotemporal Dementia and Alzheimer Disease. Neurology 96:e1743–e54. https://doi.org/10.1212/WNL.0000000000011638CrossRefPubMed

72.

Mahoney CJ, Ridgway GR, Malone IB, Downey LE, Beck J, Kinnunen KM, Schmitz N, Golden HL, Rohrer JD, Schott JM, Rossor MN, Ourselin S, Mead S, Fox NC, Warren JD (2014) Profiles of white matter tract pathology in frontotemporal dementia. Hum Brain Mapp 35:4163–4179. https://doi.org/10.1002/hbm.22468CrossRefPubMedPubMedCentral

73.

Lam BY, Halliday GM, Irish M, Hodges JR, Piguet O (2014) Longitudinal white matter changes in frontotemporal dementia subtypes. Hum Brain Mapp 35:3547–3557CrossRefPubMed

74.

Lok HC, Kwok JB (2021) The role of White Matter Dysfunction and Leukoencephalopathy/Leukodystrophy genes in the aetiology of Frontotemporal Dementias: implications for Novel Approaches to therapeutics. Int J Mol Sci 22. https://doi.org/10.3390/ijms22052541

75.

Sud M, Fahy E, Cotter D, Azam K, Vadivelu I, Burant C, Edison A, Fiehn O, Higashi R, Nair KS, Sumner S, Subramaniam S (2016) Metabolomics Workbench: an international repository for metabolomics data and metadata, metabolite standards, protocols, tutorials and training, and analysis tools. Nucleic Acids Res 44:D463–D470. https://doi.org/10.1093/nar/gkv1042CrossRefPubMed

Title: Disrupted myelin lipid metabolism differentiates frontotemporal dementia caused by GRN and C9orf72 gene mutations
Authors: Oana C. Marian
Jonathan D. Teo
Jun Yup Lee
Huitong Song
John B. Kwok
Ramon Landin-Romero
Glenda Halliday
Anthony S. Don
Publication date: 01-12-2023
Publisher: BioMed Central
Keywords: Frontotemporal Dementia
Frontotemporal Dementia
Published in: Acta Neuropathologica Communications / Issue 1/2023
Electronic ISSN: 2051-5960
DOI: https://doi.org/10.1186/s40478-023-01544-7

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Disrupted myelin lipid metabolism differentiates frontotemporal dementia caused by GRN and C9orf72 gene mutations

Abstract

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Abstract

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