Các con đường tín hiệu tế bào trong bệnh leukodystrophy tự chủ trội (ADLD): vai trò hấp dẫn của tế bào hình sao

Cellular and Molecular Life Sciences - Tập 78 - Trang 2781-2795 - 2020
Stefano Ratti1, Isabella Rusciano1, Sara Mongiorgi1, Eric Owusu Obeng1, Alessandra Cappellini1, Gabriella Teti2, Mirella Falconi2, Lia Talozzi3, Sabina Capellari2,4, Anna Bartoletti-Stella4, Pietro Guaraldi4, Pietro Cortelli2,4, Pann-Ghill Suh5,6, Lucio Cocco1, Lucia Manzoli1, Giulia Ramazzotti1
1Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy
2Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy
3Functional MR Unit, Department of Biomedical and NeuroMotor Sciences (DiBiNeM), University of Bologna, Bologna, Italy
4IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC NeuroMet, Bologna, Italy
5Korea Brain Research Institute, Daegu, Republic of Korea
6School of Life Sciences, UNIST, Ulsan, Republic of Korea

Tóm tắt

Leukodystrophy tự chủ trội (ADLD) là một rối loạn thoái hóa thần kinh hiếm gặp, dẫn đến tử vong, với sự biểu hiện quá mức của thành phần lamina nhân, Lamin B1 do sự sao chép hoặc mất đoạn gene LMNB1 ở vùng thượng gene. Các cơ chế phân tử chịu trách nhiệm cho sự khởi phát và phát triển của bệnh lý này vẫn chưa rõ ràng. Sự mất myelin dạng túi có vẻ là một trong những quan sát mô học quan trọng nhất của ADLD. Xét về vai trò của tế bào thần kinh đệm, tế bào hình sao và các con đường tín hiệu được kích hoạt bởi yếu tố ức chế bạch cầu (LIF) trong quá trình myelination, nghiên cứu này nhằm phân tích những thay đổi đặc hiệu trong các quần thể tế bào khác nhau từ bệnh nhân có sự sao chép LMNB1 và các mô hình tế bào được kỹ thuật hóa thừa hưởng protein Lamin B1. Kết quả của chúng tôi chỉ ra lần đầu tiên rằng tế bào hình sao có thể đóng vai trò quan trọng trong sự tiến triển của bệnh. Thật vậy, các tế bào từ bệnh nhân ADLD và tế bào hình sao biểu hiện quá mức LMNB1 cho thấy những thay đổi cấu trúc hạt nhân nghiêm trọng, không có ở tế bào thần kinh đệm biểu hiện quá mức LMNB1. Hơn nữa, sự tích tụ của Lamin B1 trong tế bào hình sao dẫn đến giảm nồng độ LIF và nồng độ thụ thể LIF (LIF-R), dẫn đến giảm tiết LIF. Do đó, trong cả hai mô hình tế bào của chúng tôi, các trục Jak/Stat3 và PI3K/Akt, ở cuối đường tín hiệu LIF/LIF-R, đều bị điều chỉnh giảm. Đáng chú ý rằng, việc quản lý LIF ngoại sinh có thể đảo ngược một phần các tác động độc hại do sự tích tụ của Lamin B1 gây ra, với sự khác biệt giữa tế bào hình sao và tế bào thần kinh đệm, làm nổi bật rằng sự biểu hiện quá mức LMNB1 có tác động nghiêm trọng đến chức năng của tế bào hình sao, giảm sự hỗ trợ cơ bản của chúng đối với tế bào thần kinh đệm trong quá trình myelination. Ngoài ra, sự viêm cũng được nghiên cứu, cho thấy sự kích hoạt tăng lên trong các tế bào của bệnh nhân ADLD.

Từ khóa


Tài liệu tham khảo

Padiath QS, Saigoh K, Schiffmann R et al (2006) Lamin B1 duplications cause autosomal dominant leukodystrophy. Nat Genet 38:1114–1123. https://doi.org/10.1038/ng1872 Nahhas N, Sabet Rasekh P, Vanderver A, Padiath Q (1993) Autosomal dominant leukodystrophy with autonomic disease. University of Washington, Seattle Zanigni S, Terlizzi R, Tonon C et al (2015) Brain magnetic resonance metabolic and microstructural changes in adult-onset autosomal dominant leukodystrophy. Brain Res Bull 117:24–31. https://doi.org/10.1016/j.brainresbull.2015.07.002 Köhler W, Curiel J, Vanderver A (2018) Adulthood leukodystrophies. Nat Rev Neurol 14:94–105 Zhang Y, Li J, Bai R et al (2019) LMNB1-related adult-onset autosomal dominant leukodystrophy presenting as movement disorder: a case report and review of the literature. Front Neurosci 13:1030. https://doi.org/10.3389/fnins.2019.01030 Dai Y, Ma Y, Li S et al (2017) An LMNB1 duplication caused adult-onset autosomal dominant leukodystrophy in Chinese family: clinical manifestations, neuroradiology and genetic diagnosis. Front Mol Neurosci. https://doi.org/10.3389/fnmol.2017.00215 Sandoval-Rodríguez V, Cansino-Torres MA, Sáenz-Farret M et al (2017) Autosomal dominant leukodystrophy presenting as Alzheimer’s-type dementia. Mult Scler Relat Disord 17:230–233. https://doi.org/10.1016/j.msard.2017.08.014 Brussino A, Vaula G, Cagnoli C et al (2010) A family with autosomal dominant leukodystrophy linked to 5q23.2-q23.3 without lamin B1 mutations. Eur J Neurol 17:541–549. https://doi.org/10.1111/j.1468-1331.2009.02844.x Giorgio E, Robyr D, Spielmann M et al (2015) A large genomic deletion leads to enhancer adoption by the lamin B1 gene: a second path to autosomal dominant adult-onset demyelinating leukodystrophy (ADLD). Hum Mol Genet 24:3143–3154. https://doi.org/10.1093/hmg/ddv065 Nmezi B, Giorgio E, Raininko R et al (2019) Genomic deletions upstream of lamin B1 lead to atypical autosomal dominant leukodystrophy. Neurol Genet 5:e305. https://doi.org/10.1212/NXG.0000000000000305 Padiath QS, Fu Y-H (2010) Autosomal dominant leukodystrophy caused by lamin B1 duplications a clinical and molecular case study of altered nuclear function and disease. Methods Cell Biol 98:337–357. https://doi.org/10.1016/S0091-679X(10)98014-X Finnsson J, Sundblom J, Dahl N et al (2015) LMNB1-related autosomal-dominant leukodystrophy: clinical and radiological course. Ann Neurol 78:412–425. https://doi.org/10.1002/ana.24452 Padiath QS (2019) Autosomal dominant leukodystrophy: a disease of the nuclear lamina. Front cell Dev Biol 7:41. https://doi.org/10.3389/fcell.2019.00041 Terlizzi R, Calandra-Buonaura G, Zanigni S et al (2016) A longitudinal study of a family with adult-onset autosomal dominant leukodystrophy: Clinical, autonomic and neuropsychological findings. Auton Neurosci 195:20–26. https://doi.org/10.1016/j.autneu.2016.02.005 Guaraldi P, Donadio V, Capellari S et al (2011) Isolated noradrenergic failure in adult-onset autosomal dominant leukodystrophy. Auton Neurosci Basic Clin 159:123–126. https://doi.org/10.1016/j.autneu.2010.07.011 Eldridge R, Anayiotos CP, Schlesinger S et al (1984) Hereditary adult-onset leukodystrophy simulating chronic progressive multiple sclerosis. N Engl J Med 311:948–953. https://doi.org/10.1056/NEJM198410113111504 Schwankhaus JD, Patronas N, Dorwart R et al (1988) Computed tomography and magnetic resonance imaging in adult-onset leukodystrophy. Arch Neurol 45:1004–1008. https://doi.org/10.1001/archneur.1988.00520330094015 Coffeen CM, McKenna CE, Koeppen AH et al (2000) Genetic localization of an autosomal dominant leukodystrophy mimicking chronic progressive multiple sclerosis to chromosome 5q31. Hum Mol Genet 9:787–793 Melberg A, Hallberg L, Kalimo H, Raininko R (2006) MR characteristics and neuropathology in adult-onset autosomal dominant leukodystrophy with autonomic symptoms. AJNR Am J Neuroradiol 27:904–911 Alturkustani M, Sharma M, Hammond R, Ang LC (2013) Adult-Onset leukodystrophy: review of 3 clinicopathologic phenotypes and a proposed classification. J Neuropathol Exp Neurol 72:1090–1103. https://doi.org/10.1097/NEN.0000000000000008 Giorgio E, Rolyan H, Kropp L et al (2013) Analysis of LMNB1 duplications in autosomal dominant leukodystrophy provides insights into duplication mechanisms and allele-specific expression. Hum Mutat 34:1160–1171. https://doi.org/10.1002/humu.22348 Duncan ID, Radcliff AB (2016) Inherited and acquired disorders of myelin: The underlying myelin pathology. Exp Neurol 283:452–475 Philips T, Rothstein JD (2017) Oligodendroglia: metabolic supporters of neurons. J Clin Invest 127:3271–3280 Verkhratsky A, Nedergaard M (2018) Physiology of astroglia. Physiol Rev 98:239–389. https://doi.org/10.1152/physrev.00042.2016 Ishibashi T, Dakin KA, Stevens B et al (2006) Astrocytes promote myelination in response to electrical impulses. Neuron 49:823–832. https://doi.org/10.1016/j.neuron.2006.02.006 Yue X, Wu L, Hu W (2015) The regulation of leukemia inhibitory factor. Cancer Cell Microenviron. https://doi.org/10.14800/ccm.877 Figlia G, Gerber D, Suter U (2018) Myelination and mTOR. Glia 66:693–707 Azari MF, Profyris C, Karnezis T et al (2006) Leukemia inhibitory factor arrests oligodendrocyte death and demyelination in spinal cord injury. J Neuropathol Exp Neurol 65:914–929. https://doi.org/10.1097/01.jnen.0000235855.77716.25 Banner LR, Moayeri NN, Patterson PH (1997) Leukemia inhibitory factor is expressed in astrocytes following cortical brain injury. Exp Neurol 147:1–9. https://doi.org/10.1006/exnr.1997.6536 Hendriks JJA, Slaets H, Carmans S et al (2008) Leukemia inhibitory factor modulates production of inflammatory mediators and myelin phagocytosis by macrophages. J Neuroimmunol 204:52–57. https://doi.org/10.1016/j.jneuroim.2008.07.015 Bauer S, Patterson PH (2006) Leukemia inhibitory factor promotes neural stem cell self-renewal in the adult brain. J Neurosci 26:12089–12099. https://doi.org/10.1523/JNEUROSCI.3047-06.2006 Chitnis T, Weiner HL (2017) CNS inflammation and neurodegeneration. In: journal of clinical investigation. Am Soc Clin Invest 3577–3587 Columbaro M, Mattioli E, Maraldi NM et al (2013) Oct-1 recruitment to the nuclear envelope in adult-onset autosomal dominant leukodystrophy. Biochim Biophys Acta 1832:411–420. https://doi.org/10.1016/j.bbadis.2012.12.006 Barascu A, Le Chalony C, Pennarun G et al (2012) Oxidative stress induces an ATM-independent senescence pathway through p38 MAPK-mediated lamin B1 accumulation. EMBO J 31:1080–1094. https://doi.org/10.1038/emboj.2011.492 Dreesen O, Chojnowski A, Ong PF et al (2013) Lamin B1 fluctuations have differential effects on cellular proliferation and senescence. J Cell Biol 200:605–617. https://doi.org/10.1083/jcb.201206121 Dreesen O, Ong PF, Chojnowski A, Colman A (2013) The contrasting roles of lamin B1 in cellular aging and human disease. Nucleus 4:283–290. https://doi.org/10.4161/nucl.25808 Wang AS, Ong PF, Chojnowski A et al (2017) Loss of lamin B1 is a biomarker to quantify cellular senescence in photoaged skin. Sci Rep. https://doi.org/10.1038/s41598-017-15901-9 Chojnowski A, Ong PF, Dreesen O (2015) Nuclear lamina remodelling and its implications for human disease. Cell Tissue Res 360:621–631. https://doi.org/10.1007/s00441-014-2069-4 Camps J, Erdos MR, Ried T (2015) The role of lamin Bl for the maintenance of nuclear structure and function. Nucleus 6:8–14. https://doi.org/10.1080/19491034.2014.1003510 Lin S-T, Heng MY, Ptáček LJ, Fu Y-H (2014) Regulation of Myelination in the Central Nervous System by Nuclear Lamin B1 and Non-coding RNAs. Transl Neurodegener 3:4. https://doi.org/10.1186/2047-9158-3-4 Giacomini C, Mahajani S, Ruffilli R et al (2016) Lamin B1 protein is required for dendrite development in primary mouse cortical neurons. Mol Biol Cell 27:35–47. https://doi.org/10.1091/mbc.E15-05-0307 Fukuda S, Kondo T, Takebayashi H, Taga T (2004) Negative regulatory effect of an oligodendrocytic bHLH factor OLIG2 on the astrocytic differentiation pathway. Cell Death Differ 11:196–202. https://doi.org/10.1038/sj.cdd.4401332 Stephens AD, Banigan EJ, Marko JF (2019) Chromatin’s physical properties shape the nucleus and its functions. Curr Opin Cell Biol 58:76–84. https://doi.org/10.1016/j.ceb.2019.02.006 Padiath QS (2016) Lamin B1 mediated demyelination: Linking Lamins, Lipids and Leukodystrophies. Nucleus 7:547–553. https://doi.org/10.1080/19491034.2016.1260799 Mezaki N, Miura T, Ogaki K et al (2018) Duplication and deletion upstream of LMNB1 in autosomal dominant adult-onset leukodystrophy. Neurol Genet 4:e292. https://doi.org/10.1212/NXG.0000000000000292 Ferrera D, Canale C, Marotta R et al (2014) Lamin B1 overexpression increases nuclear rigidity in autosomal dominant leukodystrophy fibroblasts. FASEB J 28:3906–3918. https://doi.org/10.1096/fj.13-247635 Lo Martire V, Alvente S, Bastianini S et al (2018) Mice overexpressing lamin B1 in oligodendrocytes recapitulate the age-dependent motor signs, but not the early autonomic cardiovascular dysfunction of autosomal-dominant leukodystrophy (ADLD). Exp Neurol 301:1–12. https://doi.org/10.1016/j.expneurol.2017.12.006 Bartoletti-Stella A, Gasparini L, Giacomini C et al (2015) Messenger RNA processing is altered in autosomal dominant leukodystrophy. Hum Mol Genet 24:2746–2756. https://doi.org/10.1093/hmg/ddv034 Tofaris GK, Patterson PH, Jessen KR, Mirsky R (2002) Denervated Schwann cells attract macrophages by secretion of leukemia inhibitory factor (LIF) and monocyte chemoattractant protein-1 in a process regulated by interleukin-6 and LIF. J Neurosci 22:6696–6703. https://doi.org/10.1523/jneurosci.22-15-06696.2002 Rittchen S, Boyd A, Burns A et al (2015) Myelin repair invivo is increased by targeting oligodendrocyte precursor cells with nanoparticles encapsulating leukaemia inhibitory factor (LIF). Biomaterials 56:78–85. https://doi.org/10.1016/j.biomaterials.2015.03.044 Roe C (2017) Unwrapping neurotrophic cytokines and histone modification. Cell Mol Neurobiol. https://doi.org/10.1007/s10571-016-0330-y Aloisi F, Rosa S, Testa U et al (1994) Regulation of leukemia inhibitory factor synthesis in cultured human astrocytes. J Immunol 152:5022–5031 Butzkueven H, Zhang JG, Soilu-Hanninen M et al (2002) LIF receptor signaling limits immune-mediated demyelination by enhancing oligodendrocyte survival. Nat Med 8:613–619. https://doi.org/10.1038/nm0602-613 Butzkueven H, Emery B, Cipriani T et al (2006) Endogenous leukemia inhibitory factor production limits autoimmune demyelination and oligodendrocyte loss. Glia 53:696–703. https://doi.org/10.1002/glia.20321 Shimi T, Goldman RD (2014) Nuclear lamins and oxidative stress in cell proliferation and longevity. Adv Exp Med Biol 773:415–430. https://doi.org/10.1007/978-1-4899-8032-8_19 Ratti S, Follo MY, Ramazzotti G et al (2019) Nuclear phospholipase C isoenzyme imbalance leads to pathologies in brain, hematologic, neuromuscular, and fertility disorders. J Lipid Res 60:312–317. https://doi.org/10.1194/jlr.R089763 Fiume R, Ramazzotti G, Teti G et al (2009) Involvement of nuclear PLCbeta1 in lamin B1 phosphorylation and G2/M cell cycle progression. FASEB J 23:957–966. https://doi.org/10.1096/fj.08-121244 Ratti S, Ramazzotti G, Faenza I et al (2018) Nuclear inositide signaling and cell cycle. Adv Biol Regul 67:1–6. https://doi.org/10.1016/j.jbior.2017.10.008 Giorgio E, Lorenzati M, di Val R, Cervo P et al (2019) Allele-specific silencing as treatment for gene duplication disorders: proof-of-principle in autosomal dominant leukodystrophy. Brain. https://doi.org/10.1093/brain/awz139