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Activating cannabinoid receptor 2 preserves axonal health through GSK-3β/NRF2 axis in adrenoleukodystrophy

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Abstract

Aberrant endocannabinoid signaling accompanies several neurodegenerative disorders, including multiple sclerosis. Here, we report altered endocannabinoid signaling in X-linked adrenoleukodystrophy (X-ALD), a rare neurometabolic demyelinating syndrome caused by malfunction of the peroxisomal ABCD1 transporter, resulting in the accumulation of very long-chain fatty acids (VLCFAs). We found abnormal levels of cannabinoid receptor 2 (CB2r) and related endocannabinoid enzymes in the brain and peripheral blood mononuclear cells (PBMCs) of X-ALD patients and in the spinal cord of a murine model of X-ALD. Preclinical treatment with a selective agonist of CB2r (JWH133) halted axonal degeneration and associated locomotor deficits, along with normalization of microgliosis. Moreover, the drug improved the main metabolic disturbances underlying this model, particularly in redox and lipid homeostatic pathways, including increased lipid droplets in motor neurons, through the modulation of the GSK-3β/NRF2 axis. JWH133 inhibited Reactive Oxygen Species elicited by excess VLCFAs in primary microglial cultures of Abcd1-null mice. Furthermore, we uncovered intertwined redox and CB2r signaling in the murine spinal cords and in patient PBMC samples obtained from a phase II clinical trial with antioxidants (NCT01495260). These findings highlight CB2r signaling as a potential therapeutic target for X-ALD and perhaps other neurodegenerative disorders that present with dysregulated redox and lipid homeostasis.

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References

  1. Agudo J, Martin M, Roca C, Molas M, Bura AS et al (2010) Deficiency of CB2 cannabinoid receptor in mice improves insulin sensitivity but increases food intake and obesity with age. Diabetologia 53:2629–2640. https://doi.org/10.1007/s00125-010-1894-6

    Article  CAS  PubMed  Google Scholar 

  2. Aso E, Juves S, Maldonado R, Ferrer I (2013) CB2 cannabinoid receptor agonist ameliorates Alzheimer-like phenotype in AbetaPP/PS1 mice. J Alzheimers Dis 35:847–858. https://doi.org/10.3233/JAD-130137

    Article  CAS  PubMed  Google Scholar 

  3. Attarian S, Young P, Brannagan TH, Adams D, Van Damme P et al (2021) A double-blind, placebo-controlled, randomized trial of PXT3003 for the treatment of Charcot-Marie-Tooth type 1A. Orphanet J Rare Dis 16:433. https://doi.org/10.1186/s13023-021-02040-8

    Article  PubMed  PubMed Central  Google Scholar 

  4. Aubourg P, Blanche S, Jambaque I, Rocchiccioli F, Kalifa G et al (1990) Reversal of early neurologic and neuroradiologic manifestations of X-linked adrenoleukodystrophy by bone marrow transplantation. N Engl J Med 322:1860–1866. https://doi.org/10.1056/NEJM199006283222607

    Article  CAS  PubMed  Google Scholar 

  5. Bailey AP, Koster G, Guillermier C, Hirst EM, MacRae JI et al (2015) Antioxidant Role for lipid droplets in a stem cell niche of drosophila. Cell 163:340–353. https://doi.org/10.1016/j.cell.2015.09.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Barendsen RW, Dijkstra IME, Visser WF, Alders M, Bliek J et al (2020) Adrenoleukodystrophy newborn screening in the netherlands (SCAN Study): the X-factor. Front Cell Dev Biol 8:499. https://doi.org/10.3389/fcell.2020.00499

    Article  PubMed  PubMed Central  Google Scholar 

  7. Benito C, Romero JP, Tolón RM, Clemente D, Docagne F et al (2007) Cannabinoid CB1 and CB2 receptors and fatty acid amide hydrolase are specific markers of plaque cell subtypes in human multiple sclerosis. J Neurosci 27:2396–2402. https://doi.org/10.1523/jneurosci.4814-06.2007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Benito C, Tolón RM, Pazos MR, Núñez E, Castillo AI et al (2008) Cannabinoid CB2 receptors in human brain inflammation. Br J Pharmacol 153:277–285. https://doi.org/10.1038/sj.bjp.0707505

    Article  CAS  PubMed  Google Scholar 

  9. Bergner CG, van der Meer F, Winkler A, Wrzos C, Türkmen M et al (2019) Microglia damage precedes major myelin breakdown in X-linked adrenoleukodystrophy and metachromatic leukodystrophy. Glia 67:1196–1209. https://doi.org/10.1002/glia.23598

    Article  PubMed  PubMed Central  Google Scholar 

  10. Bernal-Chico A, Canedo M, Manterola A, Victoria Sánchez-Gómez M, Pérez-Samartín A et al (2015) Blockade of monoacylglycerol lipase inhibits oligodendrocyte excitotoxicity and prevents demyelination in vivo. Glia 63:163–176. https://doi.org/10.1002/glia.22742

    Article  PubMed  Google Scholar 

  11. Bouchard J, Truong J, Bouchard K, Dunkelberger D, Desrayaud S et al (2012) Cannabinoid receptor 2 signaling in peripheral immune cells modulates disease onset and severity in mouse models of Huntington’s disease. J Neurosci 32:18259–18268. https://doi.org/10.1523/jneurosci.4008-12.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Cartier N, Hacein-Bey-Abina S, Bartholomae CC, Veres G, Schmidt M et al (2009) Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science 326:818–823. https://doi.org/10.1126/science.1171242

    Article  CAS  PubMed  Google Scholar 

  13. Casasnovas C, Ruiz M, Schluter A, Naudi A, Fourcade S et al (2019) Biomarker identification, safety, and efficacy of high-dose antioxidants for adrenomyeloneuropathy: a phase II Pilot Study. Neurotherapeutics. https://doi.org/10.1007/s13311-019-00735-2

    Article  PubMed  PubMed Central  Google Scholar 

  14. Chang CL, Weigel AV, Ioannou MS, Pasolli HA, Xu CS et al (2019) Spastin tethers lipid droplets to peroxisomes and directs fatty acid trafficking through ESCRT-III. J Cell Biol 218:2583–2599. https://doi.org/10.1083/jcb.201902061

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Chmiel JF, Flume P, Downey DG, Dozor AJ, Colombo C et al (2020) Safety and efficacy of lenabasum in a phase 2 randomized, placebo-controlled trial in adults with cystic fibrosis. J Cyst Fibros. https://doi.org/10.1016/j.jcf.2020.09.008

    Article  PubMed  Google Scholar 

  16. Chung YC, Shin WH, Baek JY, Cho EJ, Baik HH et al (2016) CB2 receptor activation prevents glial-derived neurotoxic mediator production, BBB leakage and peripheral immune cell infiltration and rescues dopamine neurons in the MPTP model of Parkinson’s disease. Exp Mol Med 48:e205. https://doi.org/10.1038/emm.2015.100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Coppa A, Guha S, Fourcade S, Parameswaran J, Ruiz M et al (2020) The peroxisomal fatty acid transporter ABCD1/PMP-4 is required in the C. elegans hypodermis for axonal maintenance: a worm model for adrenoleukodystrophy. Free Radic Biol Med 152:797–809. https://doi.org/10.1016/j.freeradbiomed.2020.01.177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Cristino L, Bisogno T, Di Marzo V (2020) Cannabinoids and the expanded endocannabinoid system in neurological disorders. Nat Rev Neurol 16:9–29. https://doi.org/10.1038/s41582-019-0284-z

    Article  PubMed  Google Scholar 

  19. D’Hooghe M, Willekens B, Delvaux V, D’Haeseleer M, Guillaume D et al (2021) Sativex® (nabiximols) cannabinoid oromucosal spray in patients with resistant multiple sclerosis spasticity: the Belgian experience. BMC Neurol 21:227. https://doi.org/10.1186/s12883-021-02246-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Dhopeshwarkar A, Mackie K (2014) CB2 Cannabinoid receptors as a therapeutic target-what does the future hold? Mol Pharmacol 86:430–437. https://doi.org/10.1124/mol.114.094649

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Di Marzo V (2018) New approaches and challenges to targeting the endocannabinoid system. Nat Rev Drug Discov 17:623–639. https://doi.org/10.1038/nrd.2018.115

    Article  CAS  PubMed  Google Scholar 

  22. Eichler F, Duncan C, Musolino PL, Orchard PJ, De Oliveira S et al (2017) Hematopoietic stem-cell gene therapy for cerebral adrenoleukodystrophy. N Engl J Med 377:1630–1638. https://doi.org/10.1056/NEJMoa1700554

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Eichler FS, Ren JQ, Cossoy M, Rietsch AM, Nagpal S et al (2008) Is microglial apoptosis an early pathogenic change in cerebral X-linked adrenoleukodystrophy? Ann Neurol 63:729–742. https://doi.org/10.1002/ana.21391

    Article  PubMed  Google Scholar 

  24. Espejo-Porras F, Fernández-Ruiz J, de Lago E (2018) Analysis of endocannabinoid receptors and enzymes in the post-mortem motor cortex and spinal cord of amyotrophic lateral sclerosis patients. Amyotroph Lateral Scler Frontotemporal Degener 19:377–386. https://doi.org/10.1080/21678421.2018.1425454

    Article  CAS  PubMed  Google Scholar 

  25. Espejo-Porras F, García-Toscano L, Rodríguez-Cueto C, Santos-García I, de Lago E et al (2019) Targeting glial cannabinoid CB(2) receptors to delay the progression of the pathological phenotype in TDP-43 (A315T) transgenic mice, a model of amyotrophic lateral sclerosis. Br J Pharmacol 176:1585–1600. https://doi.org/10.1111/bph.14216

    Article  CAS  PubMed  Google Scholar 

  26. Feliú A, Bonilla Del Río I, Carrillo-Salinas FJ, Hernández-Torres G, Mestre L et al (2017) 2-Arachidonoylglycerol reduces proteoglycans and enhances remyelination in a progressive model of demyelination. J Neurosci 37:8385–8398. https://doi.org/10.1523/jneurosci.2900-16.2017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Fernandez O, Costa-Frossard L, Martínez-Ginés ML, Montero P, Prieto-González JM et al (2021) Integrated management of multiple sclerosis spasticity and associated symptoms using the spasticity-plus syndrome concept: results of a structured specialists’ discussion using the Workmat(®) methodology. Front Neurol 12:722801. https://doi.org/10.3389/fneur.2021.722801

    Article  PubMed  PubMed Central  Google Scholar 

  28. Ferrer I, Kapfhammer JP, Hindelang C, Kemp S, Troffer-Charlier N et al (2005) Inactivation of the peroxisomal ABCD2 transporter in the mouse leads to late-onset ataxia involving mitochondria, Golgi and endoplasmic reticulum damage. Hum Mol Genet 14:3565–3577. https://doi.org/10.1093/hmg/ddi384

    Article  CAS  PubMed  Google Scholar 

  29. Fourcade S, Ferrer I, Pujol A (2015) Oxidative stress, mitochondrial and proteostasis malfunction in adrenoleukodystrophy: a paradigm for axonal degeneration. Free Radic Biol Med 88:18–29. https://doi.org/10.1016/j.freeradbiomed.2015.05.041

    Article  CAS  PubMed  Google Scholar 

  30. Fourcade S, Goicoechea L, Parameswaran J, Schlüter A, Launay N et al (2020) High-dose biotin restores redox balance, energy and lipid homeostasis, and axonal health in a model of adrenoleukodystrophy. Brain Pathol 30:945–963. https://doi.org/10.1111/bpa.12869

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Fourcade S, Lopez-Erauskin J, Galino J, Duval C, Naudi A et al (2008) Early oxidative damage underlying neurodegeneration in X-adrenoleukodystrophy. Hum Mol Genet 17:1762–1773. https://doi.org/10.1093/hmg/ddn085

    Article  CAS  PubMed  Google Scholar 

  32. Fourcade S, Ruiz M, Camps C, Schluter A, Houten SM et al (2009) A key role for the peroxisomal ABCD2 transporter in fatty acid homeostasis. Am J Physiol Endocrinol Metab 296:E211-221. https://doi.org/10.1152/ajpendo.90736.2008

    Article  CAS  PubMed  Google Scholar 

  33. Galán-Ganga M, Del Río R, Jiménez-Moreno N, Díaz-Guerra M, Lastres-Becker I (2020) Cannabinoid CB(2) receptor modulation by the transcription factor NRF2 is specific in microglial cells. Cell Mol Neurobiol 40:167–177. https://doi.org/10.1007/s10571-019-00719-y

    Article  CAS  PubMed  Google Scholar 

  34. Galea E, Launay N, Portero-Otin M, Ruiz M, Pamplona R et al (2012) Oxidative stress underlying axonal degeneration in adrenoleukodystrophy: a paradigm for multifactorial neurodegenerative diseases? Biochim Biophys Acta 1822:1475–1488. https://doi.org/10.1016/j.bbadis.2012.02.005

    Article  CAS  PubMed  Google Scholar 

  35. Galino J, Ruiz M, Fourcade S, Schluter A, Lopez-Erauskin J et al (2011) Oxidative damage compromises energy metabolism in the axonal degeneration mouse model of X-adrenoleukodystrophy. Antioxid Redox Signal 15:2095–2107. https://doi.org/10.1089/ars.2010.3877

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ghosn J, Taiwo B, Seedat S, Autran B, Katlama C (2018) HIV. Lancet 392:685–697. https://doi.org/10.1016/s0140-6736(18)31311-4

    Article  PubMed  Google Scholar 

  37. Gong Y, Sasidharan N, Laheji F, Frosch M, Musolino P et al (2017) Microglial dysfunction as a key pathological change in adrenomyeloneuropathy. Ann Neurol 82:813–827. https://doi.org/10.1002/ana.25085

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Han S, Thatte J, Buzard DJ, Jones RM (2013) Therapeutic utility of cannabinoid receptor type 2 (CB(2)) selective agonists. J Med Chem 56:8224–8256. https://doi.org/10.1021/jm4005626

    Article  CAS  PubMed  Google Scholar 

  39. Han S, Thoresen L, Jung JK, Zhu X, Thatte J et al (2017) Discovery of APD371: identification of a highly potent and selective CB(2) agonist for the treatment of chronic pain. ACS Med Chem Lett 8:1309–1313. https://doi.org/10.1021/acsmedchemlett.7b00396

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Inloes JM, Hsu KL, Dix MM, Viader A, Masuda K et al (2014) The hereditary spastic paraplegia-related enzyme DDHD2 is a principal brain triglyceride lipase. Proc Natl Acad Sci USA 111:14924–14929. https://doi.org/10.1073/pnas.1413706111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Inloes JM, Kiosses WB, Wang H, Walther TC, Farese RV Jr et al (2018) Functional contribution of the spastic paraplegia-related triglyceride hydrolase DDHD2 to the formation and content of lipid droplets. Biochemistry 57:827–838. https://doi.org/10.1021/acs.biochem.7b01028

    Article  CAS  PubMed  Google Scholar 

  42. Keimpema E, Di Marzo V, Harkany T (2021) Biological basis of cannabinoid medicines. Science 374:1449–1450. https://doi.org/10.1126/science.abf6099

    Article  CAS  PubMed  Google Scholar 

  43. Kemp S, Huffnagel IC, Linthorst GE, Wanders RJ, Engelen M (2016) Adrenoleukodystrophy - neuroendocrine pathogenesis and redefinition of natural history. Nat Rev Endocrinol 12:606–615. https://doi.org/10.1038/nrendo.2016.90

    Article  CAS  PubMed  Google Scholar 

  44. Klemm RW, Norton JP, Cole RA, Li CS, Park SH et al (2013) A conserved role for atlastin GTPases in regulating lipid droplet size. Cell Rep 3:1465–1475. https://doi.org/10.1016/j.celrep.2013.04.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kong W, Li H, Tuma RF, Ganea D (2014) Selective CB2 receptor activation ameliorates EAE by reducing Th17 differentiation and immune cell accumulation in the CNS. Cell Immunol 287:1–17. https://doi.org/10.1016/j.cellimm.2013.11.002

    Article  CAS  PubMed  Google Scholar 

  46. Kuhl JS, Kupper J, Baque H, Ebell W, Gartner J et al (2018) Potential risks to stable long-term outcome of allogeneic hematopoietic stem cell transplantation for children with cerebral X-linked adrenoleukodystrophy. JAMA Netw Open 1:e180769. https://doi.org/10.1001/jamanetworkopen.2018.0769

    Article  PubMed  Google Scholar 

  47. Launay N, Aguado C, Fourcade S, Ruiz M, Grau L et al (2015) Autophagy induction halts axonal degeneration in a mouse model of X-adrenoleukodystrophy. Acta Neuropathol 129:399–415. https://doi.org/10.1007/s00401-014-1378-8

    Article  PubMed  Google Scholar 

  48. Launay N, Ruiz M, Grau L, Ortega FJ, Ilieva EV et al (2017) Tauroursodeoxycholic bile acid arrests axonal degeneration by inhibiting the unfolded protein response in X-linked adrenoleukodystrophy. Acta Neuropathol 133:283–301. https://doi.org/10.1007/s00401-016-1655-9

    Article  CAS  PubMed  Google Scholar 

  49. Liu L, Zhang K, Sandoval H, Yamamoto S, Jaiswal M et al (2015) Glial lipid droplets and ROS induced by mitochondrial defects promote neurodegeneration. Cell 160:177–190. https://doi.org/10.1016/j.cell.2014.12.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Lopez-Erauskin J, Fourcade S, Galino J, Ruiz M, Schluter A et al (2011) Antioxidants halt axonal degeneration in a mouse model of X-adrenoleukodystrophy. Ann Neurol 70:84–92. https://doi.org/10.1002/ana.22363

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Lopez-Erauskin J, Galino J, Bianchi P, Fourcade S, Andreu AL et al (2012) Oxidative stress modulates mitochondrial failure and cyclophilin D function in X-linked adrenoleukodystrophy. Brain 135:3584–3598. https://doi.org/10.1093/brain/aws292

    Article  PubMed  PubMed Central  Google Scholar 

  52. Lopez-Erauskin J, Galino J, Ruiz M, Cuezva JM, Fabregat I et al (2013) Impaired mitochondrial oxidative phosphorylation in the peroxisomal disease X-linked adrenoleukodystrophy. Hum Mol Genet 22:3296–3305. https://doi.org/10.1093/hmg/ddt186

    Article  CAS  PubMed  Google Scholar 

  53. López A, Aparicio N, Pazos MR, Grande MT, Barreda-Manso MA et al (2018) Cannabinoid CB(2) receptors in the mouse brain: relevance for Alzheimer’s disease. J Neuroinflamm 15:158. https://doi.org/10.1186/s12974-018-1174-9

    Article  CAS  Google Scholar 

  54. Lu JF, Lawler AM, Watkins PA, Powers JM, Moser AB et al (1997) A mouse model for X-linked adrenoleukodystrophy. Proc Natl Acad Sci USA 94:9366–9371. https://doi.org/10.1073/pnas.94.17.9366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Mallack EJ, Turk BR, Yan H, Price C, Demetres M et al (2021) MRI surveillance of boys with X-linked adrenoleukodystrophy identified by newborn screening: Meta-analysis and consensus guidelines. J Inherit Metab Dis 44:728–739. https://doi.org/10.1002/jimd.12356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Maresz K, Carrier EJ, Ponomarev ED, Hillard CJ, Dittel BN (2005) Modulation of the cannabinoid CB2 receptor in microglial cells in response to inflammatory stimuli. J Neurochem 95:437–445. https://doi.org/10.1111/j.1471-4159.2005.03380.x

    Article  CAS  PubMed  Google Scholar 

  57. Martín-Moreno AM, Brera B, Spuch C, Carro E, García-García L et al (2012) Prolonged oral cannabinoid administration prevents neuroinflammation, lowers β-amyloid levels and improves cognitive performance in Tg APP 2576 mice. J Neuroinflamm 9:8. https://doi.org/10.1186/1742-2094-9-8

    Article  CAS  Google Scholar 

  58. Mecha M, Carrillo-Salinas FJ, Feliú A, Mestre L, Guaza C (2016) Microglia activation states and cannabinoid system: therapeutic implications. Pharmacol Ther 166:40–55. https://doi.org/10.1016/j.pharmthera.2016.06.011

    Article  CAS  PubMed  Google Scholar 

  59. Morales P, Jagerovic N (2020) Novel approaches and current challenges with targeting the endocannabinoid system. Expert Opin Drug Discov 15:917–930. https://doi.org/10.1080/17460441.2020.1752178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Morato L, Galino J, Ruiz M, Calingasan NY, Starkov AA et al (2013) Pioglitazone halts axonal degeneration in a mouse model of X-linked adrenoleukodystrophy. Brain 136:2432–2443. https://doi.org/10.1093/brain/awt143

    Article  PubMed  PubMed Central  Google Scholar 

  61. Morato L, Ruiz M, Boada J, Calingasan NY, Galino J et al (2015) Activation of sirtuin 1 as therapy for the peroxisomal disease adrenoleukodystrophy. Cell Death Differ 22:1742–1753. https://doi.org/10.1038/cdd.2015.20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Moser AB, Fatemi A (2018) Newborn screening and emerging therapies for X-linked adrenoleukodystrophy. JAMA Neurol 75:1175–1176. https://doi.org/10.1001/jamaneurol.2018.1585

    Article  PubMed  Google Scholar 

  63. Navarrete F, García-Gutiérrez MS, Aracil-Fernández A, Lanciego JL, Manzanares J (2018) Cannabinoid CB1 and CB2 receptors, and monoacylglycerol lipase gene expression alterations in the basal ganglia of patients with Parkinson’s disease. Neurotherapeutics 15:459–469. https://doi.org/10.1007/s13311-018-0603-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Navarro-Romero A, Vázquez-Oliver A, Gomis-González M, Garzón-Montesinos C, Falcón-Moya R et al (2019) Cannabinoid type-1 receptor blockade restores neurological phenotypes in two models for Down syndrome. Neurobiol Dis 125:92–106. https://doi.org/10.1016/j.nbd.2019.01.014

    Article  CAS  PubMed  Google Scholar 

  65. Palazuelos J, Aguado T, Pazos MR, Julien B, Carrasco C et al (2009) Microglial CB2 cannabinoid receptors are neuroprotective in Huntington’s disease excitotoxicity. Brain 132:3152–3164. https://doi.org/10.1093/brain/awp239

    Article  PubMed  Google Scholar 

  66. Patti F, Chisari CG, Solaro C, Benedetti MD, Berra E et al (2020) Effects of THC/CBD oromucosal spray on spasticity-related symptoms in people with multiple sclerosis: results from a retrospective multicenter study. Neurol Sci 41:2905–2913. https://doi.org/10.1007/s10072-020-04413-6

    Article  PubMed  Google Scholar 

  67. Pennetta G, Welte MA (2018) Emerging links between lipid droplets and motor neuron diseases. Dev Cell 45:427–432. https://doi.org/10.1016/j.devcel.2018.05.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Pujol A, Ferrer I, Camps C, Metzger E, Hindelang C et al (2004) Functional overlap between ABCD1 (ALD) and ABCD2 (ALDR) transporters: a therapeutic target for X-adrenoleukodystrophy. HumMolGenet 13:2997–3006. https://doi.org/10.1093/hmg/ddh323

    Article  CAS  Google Scholar 

  69. Pujol A, Hindelang C, Callizot N, Bartsch U, Schachner M et al (2002) Late onset neurological phenotype of the X-ALD gene inactivation in mice: a mouse model for adrenomyeloneuropathy. Hum Mol Genet 11:499–505. https://doi.org/10.1093/hmg/11.5.499

    Article  CAS  PubMed  Google Scholar 

  70. Ranea-Robles P, Launay N, Ruiz M, Calingasan NY, Dumont M et al (2018) Aberrant regulation of the GSK-3beta/NRF2 axis unveils a novel therapy for adrenoleukodystrophy. EMBO Mol Med. https://doi.org/10.15252/emmm.201708604

    Article  PubMed  PubMed Central  Google Scholar 

  71. Rodríguez-Pascau L, Vilalta A, Cerrada M, Traver E, Forss-Petter S et al (2021) The brain penetrant PPARγ agonist leriglitazone restores multiple altered pathways in models of X-linked adrenoleukodystrophy. Sci Transl Med. https://doi.org/10.1126/scitranslmed.abc0555

    Article  PubMed  Google Scholar 

  72. Rossi F, Bellini G, Luongo L, Manzo I, Tolone S et al (2016) Cannabinoid receptor 2 as antiobesity target: inflammation, fat storage, and browning modulation. J Clin Endocrinol Metab 101:3469–3478. https://doi.org/10.1210/jc.2015-4381

    Article  CAS  PubMed  Google Scholar 

  73. Ruiz M, Jove M, Schluter A, Casasnovas C, Villarroya F et al (2015) Altered glycolipid and glycerophospholipid signaling drive inflammatory cascades in adrenomyeloneuropathy. Hum Mol Genet 24:6861–6876. https://doi.org/10.1093/hmg/ddv375

    Article  CAS  PubMed  Google Scholar 

  74. Schluter A, Espinosa L, Fourcade S, Galino J, Lopez E et al (2012) Functional genomic analysis unravels a metabolic-inflammatory interplay in adrenoleukodystrophy. Hum Mol Genet 21:1062–1077. https://doi.org/10.1093/hmg/ddr536

    Article  CAS  PubMed  Google Scholar 

  75. Singh I, Pujol A (2010) Pathomechanisms underlying X-adrenoleukodystrophy: a three-hit hypothesis. Brain Pathol 20:838–844. https://doi.org/10.1111/j.1750-3639.2010.00392.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Spiera R, Hummers L, Chung L, Frech TM, Domsic R et al (2020) Safety and efficacy of lenabasum in a phase II, randomized, placebo-controlled trial in adults with systemic sclerosis. Arthritis Rheumatol 72:1350–1360. https://doi.org/10.1002/art.41294

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Stevens RM, Nicholson JR, Sauer A, Nolte T, Corradini L (2019) Evaluation of the selective oral CB2 agonist CNTX-6016 for the treatment of neuropathic pain: pharmacokinetic, efficacy, and safety findings from preclinical studies. PAINWeek Abstract Book 2019. Postgrad Med 130:83–84

    Google Scholar 

  78. Tadepalle N, Rugarli EI (2021) Lipid droplets in the pathogenesis of hereditary spastic paraplegia. Front Mol Biosci 8:673977. https://doi.org/10.3389/fmolb.2021.673977

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Waldhuter N, Kohler W, Hemmati PG, Jehn C, Peceny R et al (2019) Allogeneic hematopoietic stem cell transplantation with myeloablative conditioning for adult cerebral X-linked adrenoleukodystrophy. J Inherit Metab Dis 42:313–324. https://doi.org/10.1002/jimd.12044

    Article  CAS  PubMed  Google Scholar 

  80. Wiesinger C, Eichler FS, Berger J (2015) The genetic landscape of X-linked adrenoleukodystrophy: inheritance, mutations, modifier genes, and diagnosis. Appl Clin Genet 8:109–121. https://doi.org/10.2147/TACG.S49590

    Article  PubMed  PubMed Central  Google Scholar 

  81. Xu J, Kulkarni SR, Donepudi AC, More VR, Slitt AL (2012) Enhanced Nrf2 activity worsens insulin resistance, impairs lipid accumulation in adipose tissue, and increases hepatic steatosis in leptin-deficient mice. Diabetes 61:3208–3218. https://doi.org/10.2337/db11-1716

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We are indebted to patients and families and the ELA-España for their collaboration. We are thankful to the NIH NeuroBioBank for supplying the case material used for human studies. We thank Jordi Riera, Laia Grau, and Juan-Jose Martínez (Neurometabolic Diseases Laboratory) for technical assistance. This study was funded by the Institute of Health Carlos III through projects [PI19/01008] to SF and [PI20/00759] to AP (co-funded by the European Regional Development Fund, ERDF, a way to build Europe), Miguel Servet program [CPII16/00016] to SF and [PFIS, FI18/00141] to LPS (co-funded by the European Social Fund, ESF investing in your future). This study was also funded by grants from the Spanish Ministry of Health, Social Services and Equality (EC10-137), the Autonomous Government of Catalonia [2017SGR1206], the Hesperia Foundation, CERTIS Obres i Serveis, and the Crowd funding Campaign Arnau’97 to AP. JP was a predoctoral fellow of IDIBELL. The Center for Biomedical Research on Rare Diseases (CIBERER), an initiative of the Institute of Health Carlos III, funded the position of MR. Locomotor experiments were performed by the SEFALer unit F5 led by AP, which belongs to the CIBERER structure. We thank the CERCA Program/Generalitat de Catalunya for institutional support.

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Authors and Affiliations

  1. Neurometabolic Diseases Laboratory, IDIBELL, Hospital Duran I Reynals, Gran Via 199, L’Hospitalet de Llobregat, 08908, Barcelona, Spain

    Janani Parameswaran, Leire Goicoechea, Laura Planas-Serra, Montserrat Ruiz, Cristina Guilera, Carlos Casasnovas, Aurora Pujol & Stéphane Fourcade

  2. CIBERER U759, Center for Biomedical Research On Rare Diseases, Madrid, Spain

    Janani Parameswaran, Leire Goicoechea, Laura Planas-Serra, Montserrat Ruiz, Cristina Guilera, Carlos Casasnovas, Aurora Pujol & Stéphane Fourcade

  3. Department of Cell Biology, Emory University, Atlanta, GA, 30329, USA

    Janani Parameswaran

  4. Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain

    Leire Goicoechea

  5. Farmacología Integrada y Neurociencia de Sistemas, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Barcelona, Spain

    Antoni Pastor & Rafael de la Torre

  6. Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, 10065, USA

    Noel Y. Calingasan

  7. Unitat de Farmacologia, Departament de Patologia i Terapèutica Experimental, Facultat de Medicina i Ciències de La Salut, IDIBELL-Universitat de Barcelona, C/Feixa Llarga S/N, L’Hospitalet de Llobregat, 08907, Barcelona, Spain

    Ester Aso

  8. Institute of Neurosciences, University of Barcelona, Barcelona, Spain

    Ester Aso & Isidre Ferrer

  9. Experimental Medicine Department, University of Lleida-IRBLleida, Lleida, Spain

    Jordi Boada, Reinald Pamplona & Manuel Portero-Otín

  10. Department of Pathology and Experimental Therapeutics, Faculty of Medicine, IDIBELL, University of Barcelona, L’Hospitalet de Llobregat, 08907, Barcelona, Spain

    Isidre Ferrer

  11. Center for Biomedical Research on Neurodegenerative Diseases (CIBERNED), ISCIII, Madrid, Spain

    Isidre Ferrer

  12. Neuromuscular Unit, Neurology Department, Hospital Universitari de Bellvitge, Universitat de Barcelona, L’Hospitalet de Llobregat, Barcelona, Spain

    Carlos Casasnovas

  13. Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Spain

    Aurora Pujol

Authors
  1. Janani Parameswaran
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  2. Leire Goicoechea
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  15. Aurora Pujol
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  16. Stéphane Fourcade
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Contributions

AP and SF conceived the study, oversaw the project and acquired funding. JP, LG, LPS, APa, MR, NYC, CG, and JB performed the experiments. JP, LG, LPS, APa, MR, NYC, EA, JB, RP, MPO, IF, RT, AP, and SF designed and/or interpreted aspects of the different experiments. AP and CC were Principal Investigators of the clinical trial (NCT01495260). JP, AP, and SF wrote the original draft. JP, AP, and SF reviewed and edited the manuscript. All the coauthors provided input on the manuscript.

Corresponding author

Correspondence to Aurora Pujol.

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Parameswaran, J., Goicoechea, L., Planas-Serra, L. et al. Activating cannabinoid receptor 2 preserves axonal health through GSK-3β/NRF2 axis in adrenoleukodystrophy. Acta Neuropathol 144, 241–258 (2022). https://doi.org/10.1007/s00401-022-02451-2

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  • DOI: https://doi.org/10.1007/s00401-022-02451-2

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