TY - JOUR
T1 - Cystatin B is essential for proliferation and interneuron migration in individuals with EPM1 epilepsy
AU - Di Matteo, Francesco
AU - Pipicelli, Fabrizia
AU - Kyrousi, Christina
AU - Tovecci, Isabella
AU - Penna, Eduardo
AU - Crispino, Marianna
AU - Chambery, Angela
AU - Russo, Rosita
AU - Ayo-Martin, Ane Cristina
AU - Giordano, Martina
AU - Hoffmann, Anke
AU - Ciusani, Emilio
AU - Canafoglia, Laura
AU - Götz, Magdalena
AU - Di Giaimo, Rossella
AU - Cappello, Silvia
N1 - Funding Information:
We thank the families participating in this study for their involvement. We thank Pia Johannsson for help collecting CSF; Barbara W?lfel, Vincenza Sportelli, Timucin ?zt?rk, and Andrea Steiner for their excellent technical support; Richard Vallee and Joseph Lo Turco for sharing plasmids; Lucia Trastulla for supporting CNV analysis; Davide Piccolo for help with qPCR analyses; Marialuisa Melli and Jessica Keverne for critical reading of the manuscript and Isabel Buchsbaum for critical reading of the manuscript and for generating schematic drawings; Guillermina Lopez-Bendito and Nobuaki Tamamaki for sharing mouse lines; and Jovica Ninkovic for initial suggestions and support. We also thank ERASMUS+ traineeship program, Key Action 103: Learning Mobility for Individuals within Europe, for supporting student exchange between University of Naples Federico II and Max Planck Institute of Psychiatry. This work was supported by funding from the Max Planck Society and by ?Finanziamento Ricerca di Ateneo? from University of Naples Federico II. Fabrizia Pipicelli is supported by DFG (CA 1205/4-1), and Francesco Di Matteo is supported by ERA-Net Neuron (nEUrotalk). Christina Kyrousi is supported by ERA-Net E-Rare (HETER-OMICS).
Funding Information:
We thank the families participating in this study for their involvement. We thank Pia Johannsson for help collecting CSF; Barbara Wölfel, Vincenza Sportelli, Timucin Öztürk, and Andrea Steiner for their excellent technical support; Richard Vallee and Joseph Lo Turco for sharing plasmids; Lucia Trastulla for supporting CNV analysis; Davide Piccolo for help with qPCR analyses; Marialuisa Melli and Jessica Keverne for critical reading of the manuscript and Isabel Buchsbaum for critical reading of the manuscript and for generating schematic drawings; Guillermina Lopez‐Bendito and Nobuaki Tamamaki for sharing mouse lines; and Jovica Ninkovic for initial suggestions and support. We also thank ERASMUS traineeship program, Key Action 103: Learning Mobility for Individuals within Europe, for supporting student exchange between University of Naples Federico II and Max Planck Institute of Psychiatry. This work was supported by funding from the Max Planck Society and by “Finanziamento Ricerca di Ateneo” from University of Naples Federico II. Fabrizia Pipicelli is supported by DFG (CA 1205/4‐1), and Francesco Di Matteo is supported by ERA‐Net Neuron (nEUrotalk). Christina Kyrousi is supported by ERA‐Net E‐Rare (HETER‐OMICS). +
Publisher Copyright:
© 2020 The Authors. Published under the terms of the CC BY 4.0 license.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/6/8
Y1 - 2020/6/8
N2 - 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.
AB - 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.
KW - cystatin B
KW - EPM1
KW - interneuron migration
KW - neurogenesis
KW - secretion
UR - http://www.scopus.com/inward/record.url?scp=85085091355&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85085091355&partnerID=8YFLogxK
U2 - 10.15252/emmm.201911419
DO - 10.15252/emmm.201911419
M3 - Article
C2 - 32378798
AN - SCOPUS:85085091355
VL - 12
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
SN - 1757-4676
IS - 6
M1 - e11419
ER -