title: Cystatin C rescues degenerating neurons in a cystatin B-knockout mouse model of progressive myoclonus epilepsy.
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.
authors.affiliation: Nathan S. Kline Institute, 140 Old Orangeburg Rd, Orangeburg, NY 10962, USA.
authors.forename: Gurjinder
authors.initials: G
authors.lastname: Kaur
authors.forename: Panaiyur
authors.initials: P
authors.lastname: Mohan
authors.forename: Monika
authors.initials: M
authors.lastname: Pawlik
authors.forename: Steven
authors.initials: S
authors.lastname: DeRosa
authors.forename: Jay
authors.initials: J
authors.lastname: Fajiculay
authors.forename: Shaoli
authors.initials: S
authors.lastname: Che
authors.forename: Anders
authors.initials: A
authors.lastname: Grubb
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Ginsberg
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Nixon
authors.forename: Efrat
authors.initials: E
authors.lastname: Levy
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002401:Cathepsin B / Q000235:genetics / Q000378:metabolism; D002402:Cathepsin D / Q000235:genetics / Q000378:metabolism; D055313:Cystatin B / Q000235:genetics / Q000378:metabolism*; D055316:Cystatin C / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005911:Gliosis / Q000473:pathology; D006801:Humans; D008247:Lysosomes / Q000201:enzymology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020191:Myoclonic Epilepsies, Progressive / Q000378:metabolism* / Q000473:pathology*; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D045442:Rotarod Performance Test
chemical_list: D055316:Cystatin C; D055313:Cystatin B; D002401:Cathepsin B; D002402:Cathepsin D