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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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.

Detaljer

Författare
  • Gurjinder Kaur
  • Panaiyur Mohan
  • Monika Pawlik
  • Steven Derosa
  • Jay Fajiculay
  • Shaoli Che
  • Anders Grubb
  • Stephen D Ginsberg
  • Ralph A Nixon
  • Efrat Levy
Enheter & grupper
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Cell- och molekylärbiologi
Originalspråkengelska
Sidor (från-till)2256-2267
TidskriftAmerican Journal of Pathology
Volym177
StatusPublished - 2010
PublikationskategoriForskning
Peer review utfördJa