Top

Published in:

Open Access 01-06-2024 | Spastic Paraplegia | Original Paper

Neuroinflammatory disease signatures in SPG11-related hereditary spastic paraplegia patients

Authors: Laura Krumm, Tatyana Pozner, Naime Zagha, Roland Coras, Philipp Arnold, Thanos Tsaktanis, Kathryn Scherpelz, Marie Y. Davis, Johanna Kaindl, Iris Stolzer, Patrick Süß, Mukhran Khundadze, Christian A. Hübner, Markus J. Riemenschneider, Jonathan Baets, Claudia Günther, Suman Jayadev, Veit Rothhammer, Florian Krach, Jürgen Winkler, Beate Winner, Martin Regensburger

Published in: Acta Neuropathologica | Issue 1/2024

Abstract

Biallelic loss of SPG11 function constitutes the most frequent cause of complicated autosomal recessive hereditary spastic paraplegia (HSP) with thin corpus callosum, resulting in progressive multisystem neurodegeneration. While the impact of neuroinflammation is an emerging and potentially treatable aspect in neurodegenerative diseases and leukodystrophies, the role of immune cells in SPG11–HSP patients is unknown. Here, we performed a comprehensive immunological characterization of SPG11–HSP, including examination of three human postmortem brain donations, immunophenotyping of patients’ peripheral blood cells and patient-specific induced pluripotent stem cell-derived microglia-like cells (iMGL). We delineate a previously unknown role of innate immunity in SPG11–HSP. Neuropathological analysis of SPG11–HSP patient brain tissue revealed profound microgliosis in areas of neurodegeneration, downregulation of homeostatic microglial markers and cell-intrinsic accumulation of lipids and lipofuscin in IBA1⁺ cells. In a larger cohort of SPG11–HSP patients, the ratio of peripheral classical and intermediate monocytes was increased, along with increased serum levels of IL-6 that correlated with disease severity. Stimulation of patient-specific iMGLs with IFNγ led to increased phagocytic activity compared to control iMGL as well as increased upregulation and release of proinflammatory cytokines and chemokines, such as CXCL10. On a molecular basis, we identified increased STAT1 phosphorylation as mechanism connecting IFNγ-mediated immune hyperactivation and SPG11 loss of function. STAT1 expression was increased both in human postmortem brain tissue and in an Spg11^–/– mouse model. Application of an STAT1 inhibitor decreased CXCL10 production in SPG11 iMGL and rescued their toxic effect on SPG11 neurons. Our data establish neuroinflammation as a novel disease mechanism in SPG11–HSP patients and constitute the first description of myeloid cell/ microglia activation in human SPG11–HSP. IFNγ/ STAT1-mediated neurotoxic effects of hyperreactive microglia upon SPG11 loss of function indicate that immunomodulation strategies may slow down disease progression.

Available only for authorised users

Asano N, Hampel U, Garreis F, Schröder A, Schicht M, Hammer CM et al (2018) Differentiation patterns of immortalized human meibomian gland epithelial cells in three-dimensional culture. Invest Ophthalmol Vis Sci 59:1343–1353. https://doi.org/10.1167/IOVS.17-23266CrossRefPubMed

Badanjak K, Mulica P, Smajic S, Delcambre S, Tranchevent LC, Diederich N et al (2021) iPSC-derived microglia as a model to study inflammation in idiopathic Parkinson’s disease. Front Cell Dev Biol. https://doi.org/10.3389/FCELL.2021.740758CrossRefPubMedPubMedCentral

Balashov KE, Rottman JB, Weiner HL, Hancock WW (1999) CCR5(+) and CXCR3(+) T cells are increased in multiple sclerosis and their ligands MIP-1alpha and IP-10 are expressed in demyelinating brain lesions. Proc Natl Acad Sci USA 96:6873–6878. https://doi.org/10.1073/PNAS.96.12.6873ADSCrossRefPubMedPubMedCentral

Banerjee P, Mehta AR, Nirujogi RS, Cooper J, James OG, Nanda J et al (2023) Cell-autonomous immune dysfunction driven by disrupted autophagy in C9orf72-ALS iPSC-derived microglia contributes to neurodegeneration. Sci Adv. https://doi.org/10.1126/SCIADV.ABQ0651CrossRefPubMedPubMedCentral

Bauer P, Winner B, Schüle R, Bauer C, Häfele V, Hehr U et al (2009) Identification of a heterozygous genomic deletion in the spatacsin gene in SPG11 patients using high-resolution comparative genomic hybridization. Neurogenetics 10:43–48. https://doi.org/10.1007/S10048-008-0144-2CrossRefPubMed

Belge K-U, Dayyani F, Horelt A, Siedlar M, Frankenberger M, Frankenberger B et al (2002) The proinflammatory CD14+CD16+DR++ monocytes are a major source of TNF. J Immunol 168:3536–3542. https://doi.org/10.4049/JIMMUNOL.168.7.3536CrossRefPubMed

Bettcher BM, Tansey MG, Dorothée G, Heneka MT (2021) Peripheral and central immune system crosstalk in Alzheimer disease - a research prospectus. Nat Rev Neurol 17:689–701. https://doi.org/10.1038/S41582-021-00549-XCrossRefPubMedPubMedCentral

Blackstone C (2018) Hereditary spastic paraplegia. Handb Clin Neurol 148:633–652. https://doi.org/10.1016/B978-0-444-64076-5.00041-7CrossRefPubMed

Bogdan C, Schleicher U (2006) Production of interferon-gamma by myeloid cells–fact or fancy? Trends Immunol 27:282–290. https://doi.org/10.1016/J.IT.2006.04.004CrossRefPubMed

10.

Bolger AM, Lohse M, Usadel B (2014) Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics 30:2114–2120. https://doi.org/10.1093/BIOINFORMATICS/BTU170CrossRefPubMedPubMedCentral

11.

Boriero D, Carcereri de Prati A, Antonini L, Ragno R, Sohji K, Mariotto S et al (2021) The anti-STAT1 polyphenol myricetin inhibits M1 microglia activation and counteracts neuronal death. FEBS J 288:2347–2359. https://doi.org/10.1111/FEBS.15577CrossRefPubMed

12.

Böttcher C, Fernández-Zapata C, Schlickeiser S, Kunkel D, Schulz AR, Mei HE et al (2019) Multi-parameter immune profiling of peripheral blood mononuclear cells by multiplexed single-cell mass cytometry in patients with early multiple sclerosis. Sci Rep. https://doi.org/10.1038/S41598-019-55852-XCrossRefPubMedPubMedCentral

13.

Boutry M, Branchu J, Lustremant C, Pujol C, Pernelle J, Matusiak R et al (2018) Inhibition of lysosome membrane recycling causes accumulation of gangliosides that contribute to neurodegeneration. Cell Rep 23:3813–3826. https://doi.org/10.1016/j.celrep.2018.05.098PM-29949766CrossRefPubMed

14.

Boutry M, Pierga A, Matusiak R, Branchu J, Houllegatte M, Ibrahim Y et al (2019) Loss of spatacsin impairs cholesterol trafficking and calcium homeostasis. Commun Biol. https://doi.org/10.1038/S42003-019-0615-ZCrossRefPubMedPubMedCentral

15.

Branchu J, Boutry M, Sourd L, Depp M, Leone C, Corriger A et al (2017) Loss of spatacsin function alters lysosomal lipid clearance leading to upper and lower motor neuron degeneration. Neurobiol Dis 102:21–37. https://doi.org/10.1016/j.nbd.2017.02.007PM-28237315CrossRefPubMedPubMedCentral

16.

Brosseron F, Krauthausen M, Kummer M, Heneka MT (2014) Body fluid cytokine levels in mild cognitive impairment and Alzheimer’s disease: a comparative overview. Mol Neurobiol 50:534–544. https://doi.org/10.1007/S12035-014-8657-1CrossRefPubMedPubMedCentral

17.

Butturini E, Boriero D, Carcereri de Prati A, Mariotto S (2019) STAT1 drives M1 microglia activation and neuroinflammation under hypoxia. Arch Biochem Biophys 669:22–30. https://doi.org/10.1016/J.ABB.2019.05.011CrossRefPubMed

18.

Chang J, Lee S, Blackstone C (2014) Spastic paraplegia proteins spastizin and spatacsin mediate autophagic lysosome reformation. J Clin Invest 124:5249–5262. https://doi.org/10.1172/JCI77598PM-25365221M4-CitaviCrossRefPubMedPubMedCentral

19.

Chen X, Firulyova M, Manis M, Herz J, Smirnov I, Aladyeva E et al (2023) Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy. Nature 615:668–677. https://doi.org/10.1038/S41586-023-05788-0ADSCrossRefPubMed

20.

Cho J, Nelson TE, Bajova H, Gruol DL (2009) Chronic CXCL10 alters neuronal properties in rat hippocampal culture. J Neuroimmunol 207:92–100. https://doi.org/10.1016/J.JNEUROIM.2008.12.007CrossRefPubMedPubMedCentral

21.

Christensen JE, de Lemos C, Moos T, Christensen JP, Thomsen AR (2006) CXCL10 is the key ligand for CXCR3 on CD8+ effector T cells involved in immune surveillance of the lymphocytic choriomeningitis virus-infected central nervous system. J Immunol 176:4235–4243. https://doi.org/10.4049/JIMMUNOL.176.7.4235CrossRefPubMed

22.

Clark DN, Begg LR, Filiano AJ (2022) Unique aspects of IFN-γ/STAT1 signaling in neurons. Immunol Rev 311:187–204. https://doi.org/10.1111/IMR.13092CrossRefPubMedPubMedCentral

23.

Deczkowska A, Keren-Shaul H, Weiner A, Colonna M, Schwartz M, Amit I (2018) Disease-associated microglia: a universal immune sensor of neurodegeneration. Cell 173:1073–1081. https://doi.org/10.1016/j.cell.2018.05.003PM-29775591CrossRefPubMed

24.

Delgado M (2003) Inhibition of interferon (IFN) gamma-induced Jak-STAT1 activation in microglia by vasoactive intestinal peptide: inhibitory effect on CD40, IFN-induced protein-10, and inducible nitric-oxide synthase expression. J Biol Chem 278:27620–27629. https://doi.org/10.1074/JBC.M303199200CrossRefPubMed

25.

Denora PS, Smets K, Zolfanelli F, De GCC, Casali C, Deconinck T et al (2016) Motor neuron degeneration in spastic paraplegia 11 mimics amyotrophic lateral sclerosis lesions. Brain 139:1723–1734. https://doi.org/10.1093/BRAIN/AWW061CrossRefPubMedPubMedCentral

26.

Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S et al (2013) STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29:15–21. https://doi.org/10.1093/BIOINFORMATICS/BTS635CrossRefPubMed

27.

Dolan MJ, Therrien M, Jereb S, Kamath T, Gazestani V, Atkeson T et al (2023) Exposure of iPSC-derived human microglia to brain substrates enables the generation and manipulation of diverse transcriptional states in vitro. Nat Immunol 24:1382–1390. https://doi.org/10.1038/S41590-023-01558-2CrossRefPubMedPubMedCentral

28.

Faber I, Martinez ARM, de Rezende TJR, Martins CR, Martins MP, Lourenço CM et al (2018) SPG11 mutations cause widespread white matter and basal ganglia abnormalities, but restricted cortical damage. NeuroImage Clin 19:848–857. https://doi.org/10.1016/J.NICL.2018.05.031CrossRefPubMedPubMedCentral

29.

Fischer HJ, Finck TLK, Pellkofer HL, Reichardt HM, Lühder F (2019) Glucocorticoid therapy of multiple sclerosis patients induces anti-inflammatory polarization and increased chemotaxis of monocytes. Front Immunol. https://doi.org/10.3389/FIMMU.2019.01200CrossRefPubMedPubMedCentral

30.

Giaccone G, Orsi L, Cupidi C, Tagliavini F (2011) Lipofuscin hypothesis of Alzheimer’s disease. Dement Geriatr Cogn Dis Extra 1:292–296. https://doi.org/10.1159/000329544CrossRefPubMedPubMedCentral

31.

Graça FF, De Rezende TJR, Vasconcellos LFR, Pedroso JL, Barsottini OGP, França MC (2019) Neuroimaging in hereditary spastic paraplegias: current use and future perspectives. Front Neurol. https://doi.org/10.3389/FNEUR.2018.01117CrossRefPubMedPubMedCentral

32.

Grip O, Bredberg A, Lindgren S, Henriksson G (2007) Increased subpopulations of CD16(+) and CD56(+) blood monocytes in patients with active Crohn’s disease. Inflamm Bowel Dis 13:566–572. https://doi.org/10.1002/IBD.20025CrossRefPubMed

33.

Grozdanov V, Bliederhaeuser C, Ruf WP, Roth V, Fundel-Clemens K, Zondler L, Brenner D, Martin-Villalba A, Hengerer B, Kassubek J, Ludolph AC, Weishaupt JH, Danzer KM (2014) Inflammatory dysregulation of blood monocytes in Parkinson’s disease patients. Acta Neuropathol 128:651–663. https://doi.org/10.1007/S00401-014-1345-4

34.

Güner F, Pozner T, Krach F, Prots I, Loskarn S, Schlötzer-Schrehardt U et al (2021) Axon-specific mitochondrial pathology in SPG11 alpha motor neurons. Front Neurosci. https://doi.org/10.3389/FNINS.2021.680572CrossRefPubMedPubMedCentral

35.

Guzman-Martinez L, Maccioni RB, Andrade V, Navarrete LP, Pastor MG, Ramos-Escobar N (2019) Neuroinflammation as a common feature of neurodegenerative disorders. Front Pharmacol. https://doi.org/10.3389/FPHAR.2019.01008CrossRefPubMedPubMedCentral

36.

Harms AS, Ferreira SA, Romero-Ramos M (2021) Periphery and brain, innate and adaptive immunity in Parkinson’s disease. Acta Neuropathol 141:527–545. https://doi.org/10.1007/S00401-021-02268-5CrossRefPubMedPubMedCentral

37.

Hauser S, Schuster S, Heuten E, Höflinger P, Admard J, Schelling Y et al (2020) Comparative transcriptional profiling of motor neuron disorder-associated genes in various human cell culture models. Front cell Dev Biol. https://doi.org/10.3389/FCELL.2020.544043CrossRefPubMedPubMedCentral

38.

Hayakawa M, Matsubara T, Mochizuki Y, Takeuchi C, Minamitani M, Imai M et al (2022) An autopsied case report of spastic paraplegia with thin corpus callosum carrying a novel mutation in the SPG11 gene: widespread degeneration with eosinophilic inclusions. BMC Neurol. https://doi.org/10.1186/S12883-021-02514-ZCrossRefPubMedPubMedCentral

39.

Hehr U, Bauer P, Winner B, Schule R, Olmez A, Koehler W et al (2007) Long-term course and mutational spectrum of spatacsin-linked spastic paraplegia. Ann Neurol 62:656–665. https://doi.org/10.1002/ANA.21310CrossRefPubMed

40.

Höhn A, Grune T (2013) Lipofuscin: formation, effects and role of macroautophagy. Redox Biol 1:140–144. https://doi.org/10.1016/J.REDOX.2013.01.006CrossRefPubMedPubMedCentral

41.

Hörner M, Groh J, Klein D, Ilg W, Schöls L, Dos Santos S et al (2022) CNS-associated T-lymphocytes in a mouse model of Hereditary Spastic Paraplegia type 11 (SPG11) are therapeutic targets for established immunomodulators. Exp Neurol. https://doi.org/10.1016/J.EXPNEUROL.2022.114119CrossRefPubMed

42.

Hu Y, Cao C, Qin XY, Yu Y, Yuan J, Zhao Y et al (2017) Increased peripheral blood inflammatory cytokine levels in amyotrophic lateral sclerosis: a meta-analysis study. Sci Rep. https://doi.org/10.1038/S41598-017-09097-1CrossRefPubMedPubMedCentral

43.

Ivashkiv LB (2018) IFNγ: signalling, epigenetics and roles in immunity, metabolism, disease and cancer immunotherapy. Nat Rev Immunol 18:545–558. https://doi.org/10.1038/S41577-018-0029-ZCrossRefPubMedPubMedCentral

44.

Kapellos TS, Bonaguro L, Gemünd I, Reusch N, Saglam A, Hinkley ER et al (2019) Human monocyte subsets and phenotypes in major chronic inflammatory diseases. Front Immunol. https://doi.org/10.3389/FIMMU.2019.02035CrossRefPubMedPubMedCentral

45.

Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK et al (2017) A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169:1276-1290.e17. https://doi.org/10.1016/J.CELL.2017.05.018CrossRefPubMed

46.

Khundadze M, Ribaudo F, Hussain A, Stahlberg H, Brocke-Ahmadinejad N, Franzka P et al (2021) Mouse models for hereditary spastic paraplegia uncover a role of PI4K2A in autophagic lysosome reformation. Autophagy 17:3690–3706. https://doi.org/10.1080/15548627.2021.1891848CrossRefPubMedPubMedCentral

47.

King E, O’Brien JT, Donaghy P, Morris C, Barnett N, Olsen K et al (2018) Peripheral inflammation in prodromal Alzheimer’s and Lewy body dementias. J Neurol Neurosurg Psychiatry 89:339–345. https://doi.org/10.1136/JNNP-2017-317134CrossRefPubMed

48.

Klein RS, Lin E, Zhang B, Luster AD, Tollett J, Samuel MA et al (2005) Neuronal CXCL10 directs CD8+ T-cell recruitment and control of West Nile virus encephalitis. J Virol 79:11457–11466. https://doi.org/10.1128/JVI.79.17.11457-11466.2005CrossRefPubMedPubMedCentral

49.

Koper OM, Kaminska J, Sawicki K, Kemona H (2018) CXCL9, CXCL10, CXCL11, and their receptor (CXCR3) in neuroinflammation and neurodegeneration. Adv Clin Exp Med 27:849–856. https://doi.org/10.17219/ACEM/68846CrossRefPubMed

50.

Krasemann S, Madore C, Cialic R, Baufeld C, Calcagno N, El Fatimy R et al (2017) The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47:566-581.e9. https://doi.org/10.1016/J.IMMUNI.2017.08.008CrossRefPubMedPubMedCentral

51.

Krumm L, Pozner T, Kaindl J, Regensburger M, Günther C, Turan S et al (2021) Generation and characterization of an endogenously tagged SPG11-human iPSC line by CRISPR/Cas9 mediated knock-in. Stem Cell Res. https://doi.org/10.1016/J.SCR.2021.102520CrossRefPubMed

52.

Lanfer J, Kaindl J, Krumm L, Acera MG, Neurath M, Regensburger M et al (2022) Efficient and easy conversion of human iPSCs into functional induced microglia-like cells. Int J Mol Sci. https://doi.org/10.3390/IJMS23094526CrossRefPubMedPubMedCentral

53.

Lee J, Tam H, Adler L, Ilstad-Minnihan A, Macaubas C, Mellins ED (2017) The MHC class II antigen presentation pathway in human monocytes differs by subset and is regulated by cytokines. PLoS ONE. https://doi.org/10.1371/JOURNAL.PONE.0183594CrossRefPubMedPubMedCentral

54.

List J, Kohl Z, Winkler J, Marxreiter F, Doerfler A, Schmidt MA (2019) Ascending axonal degeneration of the corticospinal tract in pure hereditary spastic paraplegia: a cross-sectional DTI study. Brain Sci. https://doi.org/10.3390/BRAINSCI9100268CrossRefPubMedPubMedCentral

55.

Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25:402–408. https://doi.org/10.1006/METH.2001.1262CrossRefPubMed

56.

Lo Giudice T, Lombardi F, Santorelli FM, Kawarai T, Orlacchio A (2014) Hereditary spastic paraplegia: clinical-genetic characteristics and evolving molecular mechanisms. Exp Neurol 261:518–539. https://doi.org/10.1016/J.EXPNEUROL.2014.06.011CrossRefPubMed

57.

Lorenzini I, Alsop E, Levy J, Gittings LM, Lall D, Rabichow BE et al (2023) Moderate intrinsic phenotypic alterations in C9orf72 ALS/FTD iPSC-microglia despite the presence of C9orf72 pathological features. Front Cell Neurosci. https://doi.org/10.3389/FNCEL.2023.1179796CrossRefPubMedPubMedCentral

58.

Love MI, Huber W, Anders S (2014) Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. https://doi.org/10.1186/S13059-014-0550-8CrossRefPubMedPubMedCentral

59.

Marschallinger J, Iram T, Zardeneta M, Lee SE, Lehallier B, Haney MS et al (2020) Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain. Nat Neurosci 23:194–208. https://doi.org/10.1038/S41593-019-0566-1CrossRefPubMedPubMedCentral

60.

Mishra HK, Prots I, Havlicek S, Kohl Z, Perez-Branguli F, Boerstler T et al (2016) GSK3ß-dependent dysregulation of neurodevelopment in SPG11-patient induced pluripotent stem cell model. Ann Neurol 79:826–840. https://doi.org/10.1002/ana.24633PM-26971897CrossRefPubMedPubMedCentral

61.

Monteiro S, Roque S, Marques F, Correia-Neves M, Cerqueira JJ (2017) Brain interference: revisiting the role of IFNγ in the central nervous system. Prog Neurobiol 156:149–163. https://doi.org/10.1016/J.PNEUROBIO.2017.05.003CrossRefPubMed

62.

Mori S, Honda H, Hamasaki H, Sasagasako N, Suzuki SO, Furuya H et al (2021) Transactivation response DNA-binding protein of 43 kDa proteinopathy and lysosomal abnormalities in spastic paraplegia type 11. Neuropathology 41:253–265. https://doi.org/10.1111/NEUP.12733CrossRefPubMed

63.

Mukherjee R, Kanti Barman P, Kumar Thatoi P, Tripathy R, Kumar Das B, Ravindran B (2015) Non-classical monocytes display inflammatory features: validation in sepsis and Systemic Lupus Erythematous. Sci Rep. https://doi.org/10.1038/SREP13886CrossRefPubMedPubMedCentral

64.

Munawara U, Catanzaro M, Xu W, Tan C, Hirokawa K, Bosco N et al (2021) Hyperactivation of monocytes and macrophages in MCI patients contributes to the progression of Alzheimer’s disease. Immun Ageing. https://doi.org/10.1186/S12979-021-00236-XCrossRefPubMedPubMedCentral

65.

Nelson TE, Gruol DL (2004) The chemokine CXCL10 modulates excitatory activity and intracellular calcium signaling in cultured hippocampal neurons. J Neuroimmunol 156:74–87. https://doi.org/10.1016/J.JNEUROIM.2004.07.009CrossRefPubMed

66.

Neumann H, Boucraut J, Hahnel C, Misgeld T, Wekerle H (1996) Neuronal control of MHC class II inducibility in rat astrocytes and microglia. Eur J Neurosci 8:2582–2590. https://doi.org/10.1111/J.1460-9568.1996.TB01552.XCrossRefPubMed

67.

O’Regan GC, Farag SH, Casey CS, Wood-Kaczmar A, Pocock JM, Tabrizi SJ et al (2021) Human Huntington’s disease pluripotent stem cell-derived microglia develop normally but are abnormally hyper-reactive and release elevated levels of reactive oxygen species. J Neuroinflammation. https://doi.org/10.1186/S12974-021-02147-6CrossRefPubMedPubMedCentral

68.

Panagiotakopoulou V, Ivanyuk D, De Cicco S, Haq W, Arsić A, Yu C et al (2020) Interferon-γ signaling synergizes with LRRK2 in neurons and microglia derived from human induced pluripotent stem cells. Nat Commun. https://doi.org/10.1038/S41467-020-18755-4CrossRefPubMedPubMedCentral

69.

Panzer U, Zahner G, Wienberg U, Steinmetz OM, Peters A, Turner JE et al (2008) 15-deoxy-Delta 12,14-prostaglandin J2 inhibits INF-gamma-induced JAK/STAT1 signalling pathway activation and IP-10/CXCL10 expression in mesangial cells. Nephrol Dial Transplant 23:3776–3785. https://doi.org/10.1093/NDT/GFN361CrossRefPubMed

70.

Parodi L, Fenu S, Barbier M, Banneau G, Duyckaerts C, Du Montcel ST et al (2018) Spastic paraplegia due to SPAST mutations is modified by the underlying mutation and sex. Brain 141:3331–3342. https://doi.org/10.1093/BRAIN/AWY285CrossRefPubMed

71.

Pérez-Brangulí F, Buchsbaum IY, Pozner T, Regensburger M, Fan W, Schray A et al (2018) Human SPG11 cerebral organoids reveal cortical neurogenesis impairment. Hum Mol Genet 28:961–971. https://doi.org/10.1093/hmg/ddy397PM-30476097M4-CitaviCrossRefPubMedCentral

72.

Pérez-Brangulí F, Mishra HK, Prots I, Havlicek S, Kohl Z, Saul D et al (2014) Dysfunction of spatacsin leads to axonal pathology in SPG11-linked hereditary spastic paraplegia. Hum Mol Genet 23:4859–4874. https://doi.org/10.1093/HMG/DDU200CrossRefPubMedPubMedCentral

73.

Pizcueta P, Vergara C, Emanuele M, Vilalta A, Rodríguez-Pascau L, Martinell M (2023) Development of PPARγ agonists for the treatment of neuroinflammatory and neurodegenerative diseases: leriglitazone as a promising candidate. Int J Mol Sci. https://doi.org/10.3390/IJMS24043201CrossRefPubMedPubMedCentral

74.

Poliani PL, Wang Y, Fontana E, Robinette ML, Yamanishi Y, Gilfillan S et al (2015) TREM2 sustains microglial expansion during aging and response to demyelination. J Clin Invest 125:2161–2170. https://doi.org/10.1172/JCI77983CrossRefPubMedPubMedCentral

75.

Politis M, Lahiri N, Niccolini F, Su P, Wu K, Giannetti P et al (2015) Increased central microglial activation associated with peripheral cytokine levels in premanifest Huntington’s disease gene carriers. Neurobiol Dis 83:115–121. https://doi.org/10.1016/J.NBD.2015.08.011CrossRefPubMed

76.

Popp B, Krumbiegel M, Grosch J, Sommer A, Uebe S, Kohl Z et al (2018) Need for high-resolution genetic analysis in iPSC: results and lessons from the ForIPS consortium. Sci Rep. https://doi.org/10.1038/S41598-018-35506-0CrossRefPubMedPubMedCentral

77.

Pozner T, Schray A, Regensburger M, Lie DC, Schlötzer-Schrehardt U, Winkler J et al (2018) Tideglusib rescues neurite pathology of SPG11 iPSC derived cortical neurons. Front Neurosci. https://doi.org/10.3389/fnins.2018.00914CrossRefPubMedPubMedCentral

78.

Prinz M, Jung S, Priller J (2019) Microglia biology: one century of evolving concepts. Cell 179:292–311. https://doi.org/10.1016/J.CELL.2019.08.053CrossRefPubMed

79.

Qin XY, Zhang SP, Cao C, Loh YP, Cheng Y (2016) Aberrations in peripheral inflammatory cytokine levels in parkinson disease: a systematic review and meta-analysis. JAMA Neurol 73:1316–1324. https://doi.org/10.1001/JAMANEUROL.2016.2742CrossRefPubMed

80.

Ransohoff RM, El Khoury J (2015) Microglia in health and disease. Cold Spring Harb Perspect Biol 8:a020560. https://doi.org/10.1101/cshperspect.a020560PM-26354893CrossRefPubMed

81.

Regensburger M, Krumm L, Schmidt MA, Schmid A, Spatz IT, Marterstock DC et al (2022) Neurometabolic dysfunction in SPG11 hereditary spastic paraplegia. Nutrients. https://doi.org/10.3390/NU14224803CrossRefPubMedPubMedCentral

82.

Renvoisé B, Chang J, Singh R, Yonekawa S, FitzGibbon EJ, Mankodi A et al (2014) Lysosomal abnormalities in hereditary spastic paraplegia types SPG15 and SPG11. Ann Clin Transl Neurol 1:379–389. https://doi.org/10.1002/acn3.64PM-24999486CrossRefPubMedPubMedCentral

83.

Rossol M, Kraus S, Pierer M, Baerwald C, Wagner U (2012) The CD14(bright) CD16+ monocyte subset is expanded in rheumatoid arthritis and promotes expansion of the Th17 cell population. Arthritis Rheum 64:671–677. https://doi.org/10.1002/ART.33418CrossRefPubMed

84.

Ruschil C, Gabernet G, Lepennetier G, Heumos S, Kaminski M, Hracsko Z et al (2020) Specific induction of double negative B cells during protective and pathogenic immune responses. Front Immunol. https://doi.org/10.3389/FIMMU.2020.606338CrossRefPubMedPubMedCentral

85.

Safaiyan S, Kannaiyan N, Snaidero N, Brioschi S, Biber K, Yona S et al (2016) Age-related myelin degradation burdens the clearance function of microglia during aging. Nat Neurosci 19:995–998. https://doi.org/10.1038/NN.4325CrossRefPubMedPubMedCentral

86.

Shi Y, Kirwan P, Livesey FJ (2012) Directed differentiation of human pluripotent stem cells to cerebral cortex neurons and neural networks. Nat Protoc 7(10):1836–1846. https://doi.org/10.1038/nprot.2012.116CrossRefPubMed

87.

Sierra A, Gottfried-Blackmore AC, Mcewen BS, Bulloch K (2007) Microglia derived from aging mice exhibit an altered inflammatory profile. Glia 55:412–424. https://doi.org/10.1002/GLIA.20468CrossRefPubMed

88.

Simpson JE, Newcombe J, Cuzner ML, Woodroofe MN (2000) Expression of the interferon-gamma-inducible chemokines IP-10 and Mig and their receptor, CXCR3, in multiple sclerosis lesions. Neuropathol Appl Neurobiol 26:133–142. https://doi.org/10.1046/J.1365-2990.2000.026002133.XCrossRefPubMed

89.

Spangenberg E, Severson PL, Hohsfield LA, Crapser J, Zhang J, Burton EA et al (2019) Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model. Nat Commun. https://doi.org/10.1038/S41467-019-11674-ZCrossRefPubMedPubMedCentral

90.

Stevanin G, Santorelli FM, Azzedine H, Coutinho P, Chomilier J, Denora PS et al (2007) Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum. Nat Genet 39:366–372. https://doi.org/10.1038/ng1980PM-17322883CrossRefPubMed

91.

Strand V, Kremer J, Wallenstein G, Kanik KS, Connell C, Gruben D et al (2015) Effects of tofacitinib monotherapy on patient-reported outcomes in a randomized phase 3 study of patients with active rheumatoid arthritis and inadequate responses to DMARDs. Arthritis Res Ther. https://doi.org/10.1186/S13075-015-0825-9CrossRefPubMedPubMedCentral

92.

Strickland MR, Koller EJ, Deng DZ, Ceballos-Diaz C, Golde TE, Chakrabarty P (2018) Ifngr1 and Stat1 mediated canonical Ifn-γ signaling drives nigrostriatal degeneration. Neurobiol Dis 110:133–141. https://doi.org/10.1016/J.NBD.2017.11.007CrossRefPubMed

93.

Süb P, Lana AJ, Schlachetzki JCM (2021) Chronic peripheral inflammation: a possible contributor to neurodegenerative diseases. Neural Regen Res 16:1711–1714. https://doi.org/10.4103/1673-5374.306060CrossRef

94.

Sui Y, Stehno-Bittel L, Li S, Loganathan R, Dhillon NK, Pinson D et al (2006) CXCL10-induced cell death in neurons: role of calcium dysregulation. Eur J Neurosci 23:957–964. https://doi.org/10.1111/J.1460-9568.2006.04631.XCrossRefPubMed

95.

Trifilo MJ, Lane TE (2003) Adenovirus-mediated expression of CXCL10 in the central nervous system results in T-cell recruitment and limited neuropathology. J Neurovirol 9:315–324. https://doi.org/10.1080/13550280390201029CrossRefPubMedPubMedCentral

96.

Utz KS, Kohl Z, Marterstock DC, Doerfler A, Winkler J, Schmidt M et al (2022) Neuropsychology and MRI correlates of neurodegeneration in SPG11 hereditary spastic paraplegia. Orphanet J Rare Dis. https://doi.org/10.1186/S13023-022-02451-1CrossRefPubMedPubMedCentral

97.

Vannucchi AM, Kantarjian HM, Kiladjian JJ, Gotlib J, Cervantes F, Mesa RA et al (2015) A pooled analysis of overall survival in COMFORT-I and COMFORT-II, 2 randomized phase III trials of ruxolitinib for the treatment of myelofibrosis. Haematologica 100:1139–1145. https://doi.org/10.3324/HAEMATOL.2014.119545CrossRefPubMedPubMedCentral

98.

Vantaggiato C, Panzeri E, Castelli M, Citterio A, Arnoldi A, Santorelli FM et al (2019) ZFYVE26/SPASTIZIN and SPG11/SPATACSIN mutations in hereditary spastic paraplegia types AR-SPG15 and AR-SPG11 have different effects on autophagy and endocytosis. Autophagy 15:34–57. https://doi.org/10.1080/15548627.2018.1507438PM-30081747CrossRefPubMed

99.

Varga R-E, Khundadze M, Damme M, Nietzsche S, Hoffmann B, Stauber T et al (2015) In Vivo evidence for lysosome depletion and impaired autophagic clearance in hereditary spastic paraplegia type SPG11. PLoS Genet. https://doi.org/10.1371/journal.pgen.1005454CrossRefPubMedPubMedCentral

100.

von Bernhardi R, Eugenín-von Bernhardi L, Eugenín J (2015) Microglial cell dysregulation in brain aging and neurodegeneration. Front Aging Neurosci. https://doi.org/10.3389/FNAGI.2015.00124CrossRef

101.

Wang M, Pan W, Xu Y, Zhang J, Wan J, Jiang H (2022) Microglia-mediated neuroinflammation: a potential target for the treatment of cardiovascular diseases. J Inflamm Res 15:3083–3094. https://doi.org/10.2147/JIR.S350109CrossRefPubMedPubMedCentral

102.

Winner B, Uyanik G, Gross C, Lange M, Schulte-Mattler W, Schuierer G et al (2004) Clinical progression and genetic analysis in hereditary spastic paraplegia with thin corpus callosum in spastic gait gene 11 (SPG11). Arch Neurol 61:117–121. https://doi.org/10.1001/archneur.61.1.117PM-14732628CrossRefPubMed

103.

Wong KL, Tai JJY, Wong WC, Han H, Sem X, Yeap WH et al (2011) Gene expression profiling reveals the defining features of the classical, intermediate, and nonclassical human monocyte subsets. Blood. https://doi.org/10.1182/BLOOD-2010-12-326355CrossRefPubMedPubMedCentral

104.

Xia MQ, Bacskai BJ, Knowles RB, Qin SX, Hyman BT (2000) Expression of the chemokine receptor CXCR3 on neurons and the elevated expression of its ligand IP-10 in reactive astrocytes: In vitro ERK1/2 activation and role in Alzheimer’s disease. J Neuroimmunol 108:227–235. https://doi.org/10.1016/S0165-5728(00)00285-XCrossRefPubMed

105.

Zeiser R, von Bubnoff N, Butler J, Mohty M, Niederwieser D, Or R et al (2020) Ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease. N Engl J Med 382:1800–1810. https://doi.org/10.1056/NEJMOA1917635CrossRefPubMed

106.

Zhao Y, Ma C, Chen C, Li S, Wang Y, Yang T et al (2022) STAT1 contributes to microglial/macrophage inflammation and neurological dysfunction in a mouse model of traumatic brain injury. J Neurosci 42:7466–7481. https://doi.org/10.1523/JNEUROSCI.0682-22.2022CrossRefPubMedPubMedCentral

107.

Zhou Y-Q, Liu D-Q, Chen S-P, Sun J, Zhou X-R, Xing C et al (2019) The role of CXCR3 in neurological diseases. Curr Neuropharmacol 17:142–150. https://doi.org/10.2174/1570159X15666171109161140CrossRefPubMedPubMedCentral

108.

Zondler L, Müller K, Khalaji S, Bliederhäuser C, Ruf WP, Grozdanov V, Thiemann M, Fundel-Clemes K, Freischmidt A, Holzmann K, Strobel B, Weydt P, Witting A, Thal DR, Helferich AM, Hengerer B, Gottschalk KE, Hill O, Kluge M, Ludolph AC, Danzer KM, Weishaupt JH (2016) Peripheral monocytes are functionally altered and invade the CNS in ALS patients. Acta Neuropathol 132:391–411. https://doi.org/10.1007/s00401-016-1548-y

Title: Neuroinflammatory disease signatures in SPG11-related hereditary spastic paraplegia patients
Authors: Laura Krumm
Tatyana Pozner
Naime Zagha
Roland Coras
Philipp Arnold
Thanos Tsaktanis
Kathryn Scherpelz
Marie Y. Davis
Johanna Kaindl
Iris Stolzer
Patrick Süß
Mukhran Khundadze
Christian A. Hübner
Markus J. Riemenschneider
Jonathan Baets
Claudia Günther
Suman Jayadev
Veit Rothhammer
Florian Krach
Jürgen Winkler
Beate Winner
Martin Regensburger
Publication date: 01-06-2024
Publisher: Springer Berlin Heidelberg
Keyword: Spastic Paraplegia
Published in: Acta Neuropathologica / Issue 1/2024
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-023-02675-w

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Neuroinflammatory disease signatures in SPG11-related hereditary spastic paraplegia patients

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2024

Pituitary neuroendocrine tumors with PIT1/SF1 co-expression show distinct clinicopathological and molecular features

A new subtype of diffuse midline glioma, H3 K27 and BRAF/FGFR1 co-altered: a clinico-radiological and histomolecular characterisation

Loss of TMEM106B exacerbates Tau pathology and neurodegeneration in PS19 mice

Cryptic exon inclusion is a molecular signature of LATE-NC in aging brains

Altered TFEB subcellular localization in nigral neurons of subjects with incidental, sporadic and GBA-related Lewy body diseases

Complement and MHC patterns can provide the diagnostic framework for inflammatory neuromuscular diseases