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Di Matteo, F.* ; Pipicelli, F.* ; Kyrousi, C.* ; Tovecci, I.* ; Penna, E.* ; Crispino, M.* ; Chambery, A.* ; Russo, R.* ; Ayo-Martin, A.C.* ; Giordano, M.* ; Hoffmann, A.* ; Ciusani, E.* ; Canafoglia, L.* ; Götz, M. ; Di Giaimo, R.* ; Cappello, S.*

Cystatin B is essential for proliferation and interneuron migration in individuals with EPM1 epilepsy.

EMBO Mol. Med. 12:e11419 (2020)

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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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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Cystatin B ; Epm1 ; Interneuron Migration ; Neurogenesis ; Secretion; Progressive Myoclonus Epilepsy; Pluripotent Stem-cells; Oxidative Stress; Mouse Model; Gene; Expansion; Deficiency; Expression; Prickle1; Mutation

ISSN (print) / ISBN 1757-4676

e-ISSN 1757-4684

Journal EMBO Molecular Medicine

Quellenangaben Volume: 12, Issue: 6, Article Number: e11419

Publisher Wiley

Publishing Place Chichester

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Stem Cell Research (ISF)