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

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. Remarkably, 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 influence progenitors’ proliferation and simultaneously modulate 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 revealed by proteomic analysis in patients’ hCOs. Overall, our data shed new light on the cellular mechanisms underlying the development of EPM1.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

DISEASE(S): Progressive Myoclonus Epilepsy

SUBMITTER: Angela Chambery  

LAB HEAD: Angela Chambery

PROVIDER: PXD018021 | Pride | 2020-05-13

REPOSITORIES: Pride