Top

Published in:

Open Access 01-12-2024 | Research

Spatial transcriptomics in focal cortical dysplasia type IIb

Authors: Yujiao Wang, Yihe Wang, Linai Guo, Chunhao Shen, Yongjuan Fu, Penghu Wei, Yongzhi Shan, Qian Wu, Yue-Shan Piao, Guoguang Zhao

Published in: Acta Neuropathologica Communications | Issue 1/2024

Abstract

Focal cortical dysplasia (FCD) type IIb (FCD IIb) is an epileptogenic malformation of the neocortex that is characterized by cortical dyslamination, dysmorphic neurons (DNs) and balloon cells (BCs). Approximately 30–60% of lesions are associated with brain somatic mutations in the mTOR pathway. Herein, we investigated the transcriptional changes around the DNs and BCs regions in freshly frozen brain samples from three patients with FCD IIb by using spatial transcriptomics. We demonstrated that the DNs region in a gene enrichment network enriched for the mTOR signalling pathway, autophagy and the ubiquitin‒proteasome system, additionally which are involved in regulating membrane potential, may contribute to epileptic discharge. Moreover, differential expression analysis further demonstrated stronger expression of components of the inflammatory response and complement activation in the BCs region. And the DNs and BCs regions exhibited common functional modules, including regulation of cell morphogenesis and developmental growth. Furthermore, the expression of representative proteins in the functional enrichment module mentioned above was increased in the lesions of FCD IIb, such as p62 in DNs and BCs, UCHL1 in DNs, and C3 and CLU in BCs, which was confirmed via immunohistochemistry. Collectively, we constructed a spatial map showing the potential effects and functions of the DNs and BCs regions at the transcriptomic level and generated publicly available data on human FCD IIb to facilitate future research on human epileptogenesis.

Available only for authorised users

Ahring PK, Liao VWY, Gardella E, Johannesen KM, Krey I, Selmer KK et al (2022) Gain-of-function variants in GABRD reveal a novel pathway for neurodevelopmental disorders and epilepsy. Brain 145:1299–1309. https://doi.org/10.1093/brain/awab391CrossRefPubMed

Alten B, Zhou Q, Shin OH, Esquivies L, Lin PY, White KI et al (2021) Role of aberrant spontaneous neurotransmission in SNAP25-Associated encephalopathies. Neuron 109:59–72e55. https://doi.org/10.1016/j.neuron.2020.10.012CrossRefPubMed

Aroor A, Nguyen P, Li Y, Das R, Lugo JN, Brewster AL (2023) Assessment of tau phosphorylation and β-amyloid pathology in human drug-resistant epilepsy. Epilepsia Open 8:609–622. https://doi.org/10.1002/epi4.12744CrossRefPubMedPubMedCentral

Baldassari S, Ribierre T, Marsan E, Adle-Biassette H, Ferrand-Sorbets S, Bulteau C et al (2019) Dissecting the genetic basis of focal cortical dysplasia: a large cohort study. Acta Neuropathol 138:885–900. https://doi.org/10.1007/s00401-019-02061-5CrossRefPubMedPubMedCentral

Blauwblomme T, Dossi E, Pellegrino C, Goubert E, Iglesias BG, Sainte-Rose C et al (2019) Gamma-aminobutyric acidergic transmission underlies interictal epileptogenicity in pediatric focal cortical dysplasia. Ann Neurol 85:204–217. https://doi.org/10.1002/ana.25403CrossRefPubMed

Blumcke I, Spreafico R, Haaker G, Coras R, Kobow K, Bien CG et al (2017) Histopathological findings in brain tissue obtained during Epilepsy surgery. N Engl J Med 377:1648–1656. https://doi.org/10.1056/NEJMoa1703784CrossRefPubMed

Blumcke I, Budday S, Poduri A, Lal D, Kobow K, Baulac S (2021) Neocortical development and epilepsy: insights from focal cortical dysplasia and brain tumours. Lancet Neurol 20:943–955. https://doi.org/10.1016/s1474-4422(21)00265-9CrossRefPubMed

Blumcke I, Cendes F, Miyata H, Thom M, Aronica E, Najm I (2021) Toward a refined genotype-phenotype classification scheme for the international consensus classification of focal cortical dysplasia. Brain Pathol 31:e12956. https://doi.org/10.1111/bpa.12956CrossRefPubMedPubMedCentral

Blümcke I, Thom M, Aronica E, Armstrong DD, Vinters HV, Palmini A et al (2011) The clinicopathologic spectrum of focal cortical dysplasias: a consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission. Epilepsia 52:158–174. https://doi.org/10.1111/j.1528-1167.2010.02777.xCrossRefPubMed

10.

Cepeda C, André VM, Hauptman JS, Yamazaki I, Huynh MN, Chang JW et al (2012) Enhanced GABAergic network and receptor function in pediatric cortical dysplasia type IIB compared with tuberous sclerosis complex. Neurobiol Dis 45:310–321. https://doi.org/10.1016/j.nbd.2011.08.015CrossRefPubMed

11.

Chen WT, Lu A, Craessaerts K, Pavie B, Sala Frigerio C, Corthout N et al (2020) Spatial Transcriptomics and In Situ Sequencing to Study Alzheimer’s Disease. cell: 976–991 https://doi.org/10.1016/j.cell.2020.06.038

12.

Chen F, Swartzlander DB, Ghosh A, Fryer JD, Wang B, Zheng H (2021) Clusterin secreted from astrocyte promotes excitatory synaptic transmission and ameliorates Alzheimer’s disease neuropathology. Molecular neurodegeneration 16: 5 https://doi.org/10.1186/s13024-021-00426-7

13.

Chen TS, Lai MC, Huang HI, Wu SN, Huang CW (2022) Immunity, Ion Channels and Epilepsy. Int J Mol Sci 23:6446. https://doi.org/10.3390/ijms23126446CrossRefPubMedPubMedCentral

14.

Chen W, Zhang J, Zhang Y, Zhang J, Li W, Sha L et al (2023) Pharmacological modulation of autophagy for epilepsy therapy: opportunities and obstacles. Drug Discovery Today 28:103600. https://doi.org/10.1016/j.drudis.2023.103600CrossRefPubMed

15.

Crino PB (2011) mTOR: a pathogenic signaling pathway in developmental brain malformations. Trends Mol Med 17:734–742. https://doi.org/10.1016/j.molmed.2011.07.008CrossRefPubMed

16.

D’Antuono M, Louvel J, Köhling R, Mattia D, Bernasconi A, Olivier A et al (2004) GABAA receptor-dependent synchronization leads to ictogenesis in the human dysplastic cortex. Brain 127:1626–1640. https://doi.org/10.1093/brain/awh181CrossRefPubMed

17.

D’Gama AM, Woodworth MB, Hossain AA, Bizzotto S, Hatem NE, LaCoursiere CM et al (2017) Somatic mutations activating the mTOR pathway in dorsal telencephalic progenitors cause a continuum of cortical dysplasias. Cell Rep 21:3754–3766. https://doi.org/10.1016/j.celrep.2017.11.106CrossRefPubMedPubMedCentral

18.

De Miguel Z, Khoury N, Betley MJ, Lehallier B, Willoughby D, Olsson N et al (2021) Exercise plasma boosts memory and dampens brain inflammation via clusterin. Nature 600:494–499. https://doi.org/10.1038/s41586-021-04183-xCrossRefPubMedPubMedCentral

19.

Herold C, Bidmon HJ, Pannek HW, Hans V, Gorji A, Speckmann EJ et al (2018) ATPase N-ethylmaleimide-sensitive Fusion protein: a Novel Key Player for causing spontaneous network excitation in human temporal lobe Epilepsy. Neuroscience 371:371–383. https://doi.org/10.1016/j.neuroscience.2017.12.013CrossRefPubMed

20.

Heyne HO, Artomov M, Battke F, Bianchini C, Smith DR, Liebmann N et al (2019) Targeted gene sequencing in 6994 individuals with neurodevelopmental disorder with epilepsy. Genet Medicine: Official J Am Coll Med Genet 21:2496–2503. https://doi.org/10.1038/s41436-019-0531-0CrossRef

21.

Hwang B, Lee JH, Bang D (2018) Single-cell RNA sequencing technologies and bioinformatics pipelines. Exp Mol Med 50:1–14. https://doi.org/10.1038/s12276-018-0071-8CrossRefPubMedPubMedCentral

22.

Joglekar A, Prjibelski A, Mahfouz A, Collier P, Lin S, Schlusche AK et al (2021) A spatially resolved brain region- and cell type-specific isoform atlas of the postnatal mouse brain. Nat Commun 12:463. https://doi.org/10.1038/s41467-020-20343-5CrossRefPubMedPubMedCentral

23.

Kim JH, Park JH, Lee J, Park JW, Kim HJ, Chang WS et al (2023) Ultra-low Level somatic mutations and structural variations in focal cortical dysplasia type II. Ann Neurol 93:1082–1093. https://doi.org/10.1002/ana.26609CrossRefPubMed

24.

Kumar R, Jangir DK, Verma G, Shekhar S, Hanpude P, Kumar S et al (2017) S-nitrosylation of UCHL1 induces its structural instability and promotes α-synuclein aggregation. Sci Rep 7:44558. https://doi.org/10.1038/srep44558CrossRefPubMedPubMedCentral

25.

Lee WS, Baldassari S, Stephenson SEM, Lockhart PJ, Baulac S, Leventer RJ (2022) Cortical dysplasia and the mTOR pathway: how the study of human brain tissue has led to insights into Epileptogenesis. Int J Mol Sci 23. https://doi.org/10.3390/ijms23031344

26.

Li YF, Scerif F, Picker SR, Stone TJ, Pickles JC, Moulding DA et al (2021) Identifying cellular signalling molecules in developmental disorders of the brain: evidence from focal cortical dysplasia and tuberous sclerosis. Neuropathol Appl Neurobiol 47:781–795. https://doi.org/10.1111/nan.12715CrossRefPubMed

27.

Lim JS, Gopalappa R, Kim SH, Ramakrishna S, Lee M, Kim WI et al (2017) Somatic mutations in TSC1 and TSC2 cause focal cortical dysplasia. Am J Hum Genet 100:454–472. https://doi.org/10.1016/j.ajhg.2017.01.030CrossRefPubMedPubMedCentral

28.

Liu R, Xing Y, Zhang H, Wang J, Lai H, Cheng L et al (2022) Imbalance between the function of na(+)-K(+)-2Cl and K(+)-Cl impairs Cl(-) homeostasis in human focal cortical dysplasia. Front Mol Neurosci 15:954167. https://doi.org/10.3389/fnmol.2022.954167CrossRefPubMedPubMedCentral

29.

Maniatis S, Äijö T, Vickovic S, Braine C, Kang K, Mollbrink A et al (2019) Spatiotemporal dynamics of molecular pathology in amyotrophic lateral sclerosis. Science 364:89–93. https://doi.org/10.1126/science.aav9776CrossRefPubMed

30.

Mi Z, Graham SH (2023) Role of UCHL1 in the pathogenesis of neurodegenerative diseases and brain injury. Ageing Res Rev 86:101856. https://doi.org/10.1016/j.arr.2023.101856CrossRefPubMedPubMedCentral

31.

Mizushima N, Levine B (2020) Autophagy in Human diseases. N Engl J Med 383:1564–1576. https://doi.org/10.1056/NEJMra2022774CrossRefPubMed

32.

Mondello S, Palmio J, Streeter J, Hayes RL, Peltola J, Jeromin A (2012) Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) is increased in cerebrospinal fluid and plasma of patients after epileptic seizure. BMC Neurol 12:85. https://doi.org/10.1186/1471-2377-12-85CrossRefPubMedPubMedCentral

33.

Munson MJ, Ganley IG (2015) MTOR, PIK3C3, and autophagy: signaling the beginning from the end. Autophagy 11:2375–2376. https://doi.org/10.1080/15548627.2015.1106668CrossRefPubMedPubMedCentral

34.

Najm I, Lal D, Alonso Vanegas M, Cendes F, Lopes-Cendes I, Palmini A et al (2022) The ILAE consensus classification of focal cortical dysplasia: an update proposed by an ad hoc task force of the ILAE diagnostic methods commission. Epilepsia 63:1899–1919. https://doi.org/10.1111/epi.17301CrossRefPubMedPubMedCentral

35.

Nakashima M, Saitsu H, Takei N, Tohyama J, Kato M, Kitaura H et al (2015) Somatic mutations in the MTOR gene cause focal cortical dysplasia type IIb. Ann Neurol 78:375–386. https://doi.org/10.1002/ana.24444CrossRefPubMed

36.

Navarro JF, Croteau DL, Jurek A, Andrusivova Z, Yang B, Wang Y et al (2020) Spatial Transcriptomics reveals genes Associated with Dysregulated mitochondrial functions and stress signaling in Alzheimer Disease. iScience 23:101556. https://doi.org/10.1016/j.isci.2020.101556CrossRefPubMedPubMedCentral

37.

Ortiz C, Navarro JF, Jurek A, Märtin A, Lundeberg J, Meletis K (2020) Molecular atlas of the adult mouse brain. Sci Adv 6:eabb3446. https://doi.org/10.1126/sciadv.abb3446CrossRefPubMedPubMedCentral

38.

Pohl C, Dikic I (2019) Cellular quality control by the ubiquitin-proteasome system and autophagy. Science 366:818–822. https://doi.org/10.1126/science.aax3769CrossRefPubMed

39.

Poliquin S, Kang JQ (2022) Disruption of the ubiquitin-proteasome system and elevated endoplasmic reticulum stress in Epilepsy. Biomedicines 10:647. https://doi.org/10.3390/biomedicines10030647CrossRefPubMedPubMedCentral

40.

Rana A, Musto AE (2018) The role of inflammation in the development of epilepsy. J Neuroinflammation 15:144. https://doi.org/10.1186/s12974-018-1192-7CrossRefPubMedPubMedCentral

41.

Sim NS, Ko A, Kim WK, Kim SH, Kim JS, Shim KW et al (2019) Precise detection of low-level somatic mutation in resected epilepsy brain tissue. Acta Neuropathol 138:901–912. https://doi.org/10.1007/s00401-019-02052-6CrossRefPubMed

42.

Ståhl PL, Salmén F, Vickovic S, Lundmark A, Navarro JF, Magnusson J et al (2016) Visualization and analysis of gene expression in tissue sections by spatial transcriptomics. Science 353:78–82. https://doi.org/10.1126/science.aaf2403CrossRefPubMed

43.

Stuart T, Butler A, Hoffman P, Hafemeister C, Papalexi E, Mauck WM 3rd, et al (2019) Comprehensive Integration of Single-Cell Data. Cell 177:1888–1902e1821. https://doi.org/10.1016/j.cell.2019.05.031

44.

Tarkowski B, Kuchcinska K, Blazejczyk M, Jaworski J (2019) Pathological mTOR mutations impact cortical development. Hum Mol Genet 28:2107–2119. https://doi.org/10.1093/hmg/ddz042CrossRefPubMed

45.

Vezzani A, Fujinami RS, White HS, Preux PM, Blümcke I, Sander JW et al (2016) Infections, inflammation and epilepsy. Acta Neuropathol 131:211–234. https://doi.org/10.1007/s00401-015-1481-5CrossRefPubMed

46.

Wang Y, Wang L, Blümcke I, Zhang W, Fu Y, Shan Y et al (2022) Integrated genotype-phenotype analysis of long-term epilepsy-associated ganglioglioma. Brain Pathol 32:e13011. https://doi.org/10.1111/bpa.13011CrossRefPubMed

47.

Wang Y, Yu T, Blümcke I, Cai Y, Sun K, Gao R et al (2023) The clinico-pathological characterisation of focal cortical dysplasia type IIb genetically defined by MTOR mosaicism. Neuropathol Appl Neurobiol 49:e12874. https://doi.org/10.1111/nan.12874CrossRefPubMed

48.

Willis EF, MacDonald KPA, Nguyen QH, Garrido AL, Gillespie ER, Harley SBR et al (2020) Repopulating Microglia promote Brain Repair in an IL-6-Dependent manner. Cell 180:833–846e816. https://doi.org/10.1016/j.cell.2020.02.013CrossRefPubMed

49.

Wojtas AM, Sens JP, Kang SS, Baker KE, Berry TJ, Kurti A et al (2020) Astrocyte-derived clusterin suppresses amyloid formation in vivo. Mol Neurodegeneration 15:71. https://doi.org/10.1186/s13024-020-00416-1CrossRef

50.

Yi Z, Song Z, Xue J, Yang C, Li F, Pan H et al (2022) A heterozygous missense variant in the YWHAG gene causing developmental and epileptic encephalopathy 56 in a Chinese family. BMC Med Genom 15:216. https://doi.org/10.1186/s12920-022-01377-8CrossRef

51.

Zhang M, Cai F, Zhang S, Zhang S, Song W (2014) Overexpression of ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) delays Alzheimer’s progression in vivo. Sci Rep 4:7298. https://doi.org/10.1038/srep07298CrossRefPubMedPubMedCentral

52.

Zhang Z, Liu Q, Liu M, Wang H, Dong Y, Ji T et al (2018) Upregulation of HMGB1-TLR4 inflammatory pathway in focal cortical dysplasia type II. J Neuroinflammation 15:27. https://doi.org/10.1186/s12974-018-1078-8CrossRefPubMedPubMedCentral

53.

Zhong S, Zhao Z, Xie W, Cai Y, Zhang Y, Ding J et al (2021) GABAergic Interneuron and neurotransmission are mTOR-Dependently disturbed in experimental focal cortical dysplasia. Mol Neurobiol 58:156–169. https://doi.org/10.1007/s12035-020-02086-yCrossRefPubMed

54.

Zimmer TS, Broekaart DWM, Luinenburg M, Mijnsbergen C, Anink JJ, Sim NS et al (2021) Balloon cells promote immune system activation in focal cortical dysplasia type 2b. Neuropathol Appl Neurobiol 47:826–839. https://doi.org/10.1111/nan.12736CrossRefPubMedPubMedCentral

Title: Spatial transcriptomics in focal cortical dysplasia type IIb
Authors: Yujiao Wang
Yihe Wang
Linai Guo
Chunhao Shen
Yongjuan Fu
Penghu Wei
Yongzhi Shan
Qian Wu
Yue-Shan Piao
Guoguang Zhao
Publication date: 01-12-2024
Publisher: BioMed Central
Published in: Acta Neuropathologica Communications / Issue 1/2024
Electronic ISSN: 2051-5960
DOI: https://doi.org/10.1186/s40478-024-01897-7

DNA hypomethylator phenotype reprograms glutamatergic network in receptor tyrosine kinase gene-mutated glioblastoma

Open Access
Glioblastoma
Research

Urinary D-asparagine level is decreased by the presence of glioblastoma

Open Access
Research

Alpha-synuclein aggregates are phosphatase resistant

Open Access
Parkinson Disease
Research

Distinct forebrain regions define a dichotomous astrocytic profile in multiple system atrophy

Open Access
Research

Dysregulation of neuroprotective lipoxin pathway in astrocytes in response to cytokines and ocular hypertension

Open Access
Hypertension
Research

Correction: SNCA genetic lowering reveals differential cognitive function of alpha-synuclein dependent on sex

Open Access
Correction

Keynote webinar | Spotlight on menopause

Menopause
Video Series

Menopause can have a significant impact on the body, with effects ranging beyond the endocrine and reproductive systems. Learn about the broader systemic effects of menopause, so you can help patients in your clinics through the transition.

Prof. Martha Hickey

Dr. Claudia Barth

Dr. Samar El Khoudary

Developed by: Springer Medicine

Watch now

Advances in Alzheimer's

Alzheimer's Disease
Independent Medical Education

Alzheimer's research and care is changing rapidly. Keep up with the latest developments from key international conferences, together with expert insights on how to integrate these advances into practice.

This content is intended for healthcare professionals outside of the UK.

Supported by:

Lilly

Developed by: Springer Healthcare IME

Learn more

Keynote series | Spotlight on menopause

Springer Medicine

Spatial transcriptomics in focal cortical dysplasia type IIb

Abstract

Other articles of this Issue 1/2024

DNA hypomethylator phenotype reprograms glutamatergic network in receptor tyrosine kinase gene-mutated glioblastoma

Urinary D-asparagine level is decreased by the presence of glioblastoma

Alpha-synuclein aggregates are phosphatase resistant

Distinct forebrain regions define a dichotomous astrocytic profile in multiple system atrophy

Dysregulation of neuroprotective lipoxin pathway in astrocytes in response to cytokines and ocular hypertension

Correction: SNCA genetic lowering reveals differential cognitive function of alpha-synuclein dependent on sex

Keynote webinar | Spotlight on menopause

Advances in Alzheimer's

Keynote series | Spotlight on menopause

Springer Medicine

Abstract

Please log in to get access to this content