Cystatin B is Essential for Proliferation and Interneuron Migration in Individuals with EPM1 Epilepsy

Overview

Journal EMBO Mol Med

Specialty Molecular Biology

Date 2020 May 8

PMID 32378798

Citations 26

Authors

Francesco Di Matteo

Fabrizia Pipicelli

Christina Kyrousi

Isabella Tovecci

Eduardo Penna

Marianna Crispino

Angela Chambery

Rosita Russo

Ane Cristina Ayo-Martin

Martina Giordano

Anke Hoffmann

Emilio Ciusani

Laura Canafoglia

Magdalena Gotz

Rossella Di Giaimo

Silvia Cappello

Affiliations

Soon will be listed here.

Abstract

Progressive myoclonus epilepsy (PME) of Unverricht-Lundborg type (EPM1) is an autosomal recessive neurodegenerative disorder with the highest incidence of PME worldwide. Mutations in the gene encoding cystatin B (CSTB) are the primary genetic cause of EPM1. Here, we investigate the role of CSTB during neurogenesis in vivo in the developing mouse brain and in vitro in human cerebral organoids (hCOs) derived from EPM1 patients. We find that CSTB (but not one of its pathological variants) is secreted into the mouse cerebral spinal fluid and the conditioned media from hCOs. In embryonic mouse brain, we find that functional CSTB influences progenitors' proliferation and modulates neuronal distribution by attracting interneurons to the site of secretion via cell-non-autonomous mechanisms. Similarly, in patient-derived hCOs, low levels of functional CSTB result in an alteration of progenitor's proliferation, premature differentiation, and changes in interneurons migration. Secretion and extracellular matrix organization are the biological processes particularly affected as suggested by a proteomic analysis in patients' hCOs. Overall, our study sheds new light on the cellular mechanisms underlying the development of EPM1.

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References

Zerovnik E . Possible Mechanisms by which Stefin B could Regulate Proteostasis and Oxidative Stress. Cells. 2019; 8(1). PMC: 6357131. DOI: 10.3390/cells8010070. View

Virtaneva K, DAmato E, Miao J, Koskiniemi M, Norio R, Avanzini G . Unstable minisatellite expansion causing recessively inherited myoclonus epilepsy, EPM1. Nat Genet. 1997; 15(4):393-6. DOI: 10.1038/ng0497-393. View

Barbosa J, Di Giaimo R, Gotz M, Ninkovic J . Single-cell in vivo imaging of adult neural stem cells in the zebrafish telencephalon. Nat Protoc. 2016; 11(8):1360-70. DOI: 10.1038/nprot.2016.077. View

Koskiniemi M, Donner M, Majuri H, Haltia M, Norio R . Progressive myoclonus epilepsy. A clinical and histopathological study. Acta Neurol Scand. 1974; 50(3):307-32. View

Bassuk A, Wallace R, Buhr A, Buller A, Afawi Z, Shimojo M . A homozygous mutation in human PRICKLE1 causes an autosomal-recessive progressive myoclonus epilepsy-ataxia syndrome. Am J Hum Genet. 2008; 83(5):572-81. PMC: 2668041. DOI: 10.1016/j.ajhg.2008.10.003. View

Zhou L, Xiao X, Li S, Jia X, Wang P, Sun W . Phenotypic characterization of patients with early-onset high myopia due to mutations in or : Why not Stickler syndrome?. Mol Vis. 2018; 24:560-573. PMC: 6089037. View

Chen F, LoTurco J . A method for stable transgenesis of radial glia lineage in rat neocortex by piggyBac mediated transposition. J Neurosci Methods. 2012; 207(2):172-80. PMC: 3972033. DOI: 10.1016/j.jneumeth.2012.03.016. View

Reczek D, Schwake M, Schroder J, Hughes H, Blanz J, Jin X . LIMP-2 is a receptor for lysosomal mannose-6-phosphate-independent targeting of beta-glucocerebrosidase. Cell. 2007; 131(4):770-83. DOI: 10.1016/j.cell.2007.10.018. View

Danner N, Julkunen P, Hypponen J, Niskanen E, Saisanen L, Kononen M . Alterations of motor cortical excitability and anatomy in Unverricht-Lundborg disease. Mov Disord. 2013; 28(13):1860-7. DOI: 10.1002/mds.25615. View

10.

Shang W, Liu W, Zhao X, Sun Q, Bi J, Chi Z . Expressions of glutathione S-transferase alpha, mu, and pi in brains of medically intractable epileptic patients. BMC Neurosci. 2008; 9:67. PMC: 2490696. DOI: 10.1186/1471-2202-9-67. View

11.

Mancini G, Schot R, De Wit M, de Coo R, Oostenbrink R, Bindels-de Heus K . CSTB null mutation associated with microcephaly, early developmental delay, and severe dyskinesia. Neurology. 2016; 86(9):877-8. DOI: 10.1212/WNL.0000000000002422. View

12.

Russo R, Matrone N, Belli V, Ciardiello D, Valletta M, Esposito S . Macrophage Migration Inhibitory Factor Is a Molecular Determinant of the Anti-EGFR Monoclonal Antibody Cetuximab Resistance in Human Colorectal Cancer Cells. Cancers (Basel). 2019; 11(10). PMC: 6826402. DOI: 10.3390/cancers11101430. View

13.

Li Y, Muffat J, Omer A, Bosch I, Lancaster M, Sur M . Induction of Expansion and Folding in Human Cerebral Organoids. Cell Stem Cell. 2017; 20(3):385-396.e3. PMC: 6461394. DOI: 10.1016/j.stem.2016.11.017. View

14.

Dityatev A . Remodeling of extracellular matrix and epileptogenesis. Epilepsia. 2010; 51 Suppl 3:61-5. DOI: 10.1111/j.1528-1167.2010.02612.x. View

15.

Johansson P, Dziegielewska K, Ek C, Habgood M, Liddelow S, Potter A . Blood-CSF barrier function in the rat embryo. Eur J Neurosci. 2006; 24(1):65-76. DOI: 10.1111/j.1460-9568.2006.04904.x. View

16.

Alakurtti K, Weber E, Rinne R, Theil G, de Haan G, Lindhout D . Loss of lysosomal association of cystatin B proteins representing progressive myoclonus epilepsy, EPM1, mutations. Eur J Hum Genet. 2004; 13(2):208-15. DOI: 10.1038/sj.ejhg.5201300. View

17.

Tamamaki N, Yanagawa Y, Tomioka R, Miyazaki J, Obata K, Kaneko T . Green fluorescent protein expression and colocalization with calretinin, parvalbumin, and somatostatin in the GAD67-GFP knock-in mouse. J Comp Neurol. 2003; 467(1):60-79. DOI: 10.1002/cne.10905. View

18.

Butinar M, Prebanda M, Rajkovic J, Jeric B, Stoka V, Peters C . Stefin B deficiency reduces tumor growth via sensitization of tumor cells to oxidative stress in a breast cancer model. Oncogene. 2013; 33(26):3392-400. DOI: 10.1038/onc.2013.314. View

19.

Pennacchio L, Bouley D, Higgins K, Scott M, Noebels J, Myers R . Progressive ataxia, myoclonic epilepsy and cerebellar apoptosis in cystatin B-deficient mice. Nat Genet. 1998; 20(3):251-8. DOI: 10.1038/3059. View

20.

Boyer L, Campbell B, Larkin S, Mu Y, Gage F . Dopaminergic differentiation of human pluripotent cells. Curr Protoc Stem Cell Biol. 2012; Chapter 1:Unit1H.6. DOI: 10.1002/9780470151808.sc01h06s22. View