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

Di Matteo, F., Pipicelli, F., Kyrousi, C., Tovecci, I., Penna, E., Crispino, M., et al. (2020). Cystatin B is essential for proliferation and interneuron migration in individuals with EPM1 epilepsy. EMBO MOLECULAR MEDICINE, 12(6): e11419. doi:10.15252/emmm.201911419.

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Di Matteo, Francesco1, Author           
Pipicelli, Fabrizia1, 2, Author           
Kyrousi, Christina1, Author           
Tovecci, Isabella3, Author           
Penna, Eduardo, Author
Crispino, Marianna, Author
Chambery, Angela, Author
Russo, Rosita, Author
Ayo-Martin, Ane Cristina1, 2, Author           
Giordano, Martina3, Author           
Hoffmann, Anke4, Author           
Ciusani, Emilio, Author
Canafoglia, Laura, Author
Goetz, Magdalena, Author
Di Giaimo, Rossella1, Author           
Cappello, Silvia1, Author           
Affiliations:
1Max Planck Research Group Developmental Neurobiology (Silvia Cappello), Max Planck Institute of Psychiatry, Max Planck Society, ou_2173645              
2IMPRS Translational Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society, Kraepelinstr. 2-10, 80804 Munich, DE, ou_3318616              
3Max Planck Institute of Psychiatry, Max Planck Society, Kraepelinstr. 2-10, 80804 Munich, DE, ou_1607137              
4Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society, ou_2035295              

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Free keywords: PROGRESSIVE MYOCLONUS EPILEPSY; PLURIPOTENT STEM-CELLS; OXIDATIVE STRESS; MOUSE MODEL; GENE; EXPANSION; DEFICIENCY; EXPRESSION; PRICKLE1; MUTATIONResearch & Experimental Medicine; cystatin B; EPM1; interneuron migration; neurogenesis; secretion;
 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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Language(s): eng - English
 Dates: 2020-05-072020-06-08
 Publication Status: Published in print
 Pages: 21
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: ISI: 000530693500001
DOI: 10.15252/emmm.201911419
 Degree: -

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Title: EMBO MOLECULAR MEDICINE
Source Genre: Journal
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Publ. Info: 111 RIVER ST, HOBOKEN 07030-5774, NJ USA : WILEY
Pages: - Volume / Issue: 12 (6) Sequence Number: e11419 Start / End Page: - Identifier: ISSN: 1757-4676