Advanced

Cystatin C Rescues Degenerating Neurons in a Cystatin B-Knockout Mouse Model of Progressive Myoclonus Epilepsy.

Kaur, Gurjinder; Mohan, Panaiyur; Pawlik, Monika; Derosa, Steven; Fajiculay, Jay; Che, Shaoli; Grubb, Anders LU ; Ginsberg, Stephen D; Nixon, Ralph A and Levy, Efrat (2010) In American Journal of Pathology 177. p.2256-2267
Abstract
In vitro studies have shown that cystatin C (CysC) is neuroprotective. Here we demonstrate that CysC is neuroprotective in vivo, in a mouse model of the inherited neurodegenerative disorder, progressive myoclonic epilepsy type 1 (EPM1). Loss-of-function mutations in the cystatin B (CysB) gene, an intracellular cysteine protease inhibitor, lead to this human disease. A CysB-knockout (CysBKO) mouse model develops symptoms that mimic EPM1. CysB deficiency in these mice results in enhanced cathepsin B and D activities, indicating lysosomal dysfunction. We show that expression of CysC is enhanced in the brains of CysBKO mice. Crossbreeding of CysBKO mice with either CysC-overexpressing transgenic mice or CysC-knockout mice demonstrates that... (More)
In vitro studies have shown that cystatin C (CysC) is neuroprotective. Here we demonstrate that CysC is neuroprotective in vivo, in a mouse model of the inherited neurodegenerative disorder, progressive myoclonic epilepsy type 1 (EPM1). Loss-of-function mutations in the cystatin B (CysB) gene, an intracellular cysteine protease inhibitor, lead to this human disease. A CysB-knockout (CysBKO) mouse model develops symptoms that mimic EPM1. CysB deficiency in these mice results in enhanced cathepsin B and D activities, indicating lysosomal dysfunction. We show that expression of CysC is enhanced in the brains of CysBKO mice. Crossbreeding of CysBKO mice with either CysC-overexpressing transgenic mice or CysC-knockout mice demonstrates that clinical symptoms and neuropathologies, including motor coordination disorder, cerebellar atrophy, neuronal loss in the cerebellum and cerebral cortex, and gliosis caused by CysB deficiency, are rescued by CysC overexpression and exacerbated by CysC deficiency. Thus, CysC effectively rescues the CysB loss-of-function mutations, facilitating the reversal of pathophysiological changes and suggesting a novel therapeutic intervention for patients with EPM1 and other neurodegenerative disorders. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
American Journal of Pathology
volume
177
pages
2256 - 2267
publisher
American Society for Investigative Pathology
external identifiers
  • wos:000284182900014
  • pmid:20889561
  • scopus:78149329846
ISSN
1525-2191
DOI
10.2353/ajpath.2010.100461
language
English
LU publication?
yes
id
bf5c34fb-e3f6-40ec-bacf-8144b1115320 (old id 1711451)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/20889561?dopt=Abstract
date added to LUP
2010-11-05 12:19:51
date last changed
2018-07-15 04:18:00
@article{bf5c34fb-e3f6-40ec-bacf-8144b1115320,
  abstract     = {In vitro studies have shown that cystatin C (CysC) is neuroprotective. Here we demonstrate that CysC is neuroprotective in vivo, in a mouse model of the inherited neurodegenerative disorder, progressive myoclonic epilepsy type 1 (EPM1). Loss-of-function mutations in the cystatin B (CysB) gene, an intracellular cysteine protease inhibitor, lead to this human disease. A CysB-knockout (CysBKO) mouse model develops symptoms that mimic EPM1. CysB deficiency in these mice results in enhanced cathepsin B and D activities, indicating lysosomal dysfunction. We show that expression of CysC is enhanced in the brains of CysBKO mice. Crossbreeding of CysBKO mice with either CysC-overexpressing transgenic mice or CysC-knockout mice demonstrates that clinical symptoms and neuropathologies, including motor coordination disorder, cerebellar atrophy, neuronal loss in the cerebellum and cerebral cortex, and gliosis caused by CysB deficiency, are rescued by CysC overexpression and exacerbated by CysC deficiency. Thus, CysC effectively rescues the CysB loss-of-function mutations, facilitating the reversal of pathophysiological changes and suggesting a novel therapeutic intervention for patients with EPM1 and other neurodegenerative disorders.},
  author       = {Kaur, Gurjinder and Mohan, Panaiyur and Pawlik, Monika and Derosa, Steven and Fajiculay, Jay and Che, Shaoli and Grubb, Anders and Ginsberg, Stephen D and Nixon, Ralph A and Levy, Efrat},
  issn         = {1525-2191},
  language     = {eng},
  pages        = {2256--2267},
  publisher    = {American Society for Investigative Pathology},
  series       = {American Journal of Pathology},
  title        = {Cystatin C Rescues Degenerating Neurons in a Cystatin B-Knockout Mouse Model of Progressive Myoclonus Epilepsy.},
  url          = {http://dx.doi.org/10.2353/ajpath.2010.100461},
  volume       = {177},
  year         = {2010},
}