Neuropathological Changes in a Mouse Model of Progressive Myoclonus Epilepsy: Cystatin B Deficiency and Unverricht-Lundborg Disease

Abstract

Progressive myoclonus epilepsy of the Unverricht-Lundborg type (EPM1) is a recessively inherited neurodegenerative disease caused by loss-of-function mutations in the gene encoding cystatin B, a cysteine protease inhibitor. Mice with disruptions in this gene display myoclonic seizures, progressive ataxia, and cerebellar pathology closely paralleling EPMI in humans. To provide further insight into our understanding of EPM1, we report pathological findings in brains from cystatin B-deficient mice. In addition to confirming the loss of cerebellar granular cell neurons by apoptosis, we identified additional neuronal apoptosis in young mutant mice (3-4 months old) within the hippocampal formation and entorhinal cortex. In older mutant mice (16-18 months old), there was also gliosis most marked in the presubiculum and parasubiculum of the hippocampal formation, as well as the entorhinal cortex, neocortex, and striatum. Furthermore, widespread white matter gliosis was also noted, which may be a secondary phenomenon. Within the cerebral cortex, cellular atrophy was a prominent finding in the superficial neurons of the prosubiculum. Finally, we show that mutant mice in either a "seizure-prone" or "seizure-resistant" genetic background display similar neuropathological changes. These findings indicate that neuronal atrophy is an important consequence of cystatin-B deficiency independent of seizure events, suggesting a physiological role for this protein in the maintenance of normal neuronal structure.

Loss of lysosomal association of cystatin B proteins representing progressive myoclonus epilepsy, EPM1, mutations

“…16 The mice also show loss of cerebellar granule cells due to apoptotic cell death, 16 neuronal atrophy and apoptosis outside the cerebellum and gliosis. 17 In mice double-deficient for CSTB and cathepsin B, the amount of cerebellar apoptosis is significantly decreased, suggesting that cathepsin B contributes to the apoptotic phenotype in EPM1. 18 Moreover, seizures induce upregulation of CSTB mRNA and protein in rats.…”

Genomic and proteomic analysis of the effects of cannabinoids on normal human astrocytes

“…It has been shown that aldolase A and enolase 1 are transcribed in response to hypoxia (Semenza et al, 1996). Another protein up-regulated on treatment of NHA with Δ 9 -THC is cystatin B, important in maintaining normal neuronal architecture and size (Shannon et al, 2002). Brains of cystatin B deficient, adult mice are smaller than normal controls, and this size difference is paralleled by low body weight, a greater density of neurons in the cerebellar granular cell layer, as well as an increased susceptibility of granule cells to undergo apoptosis (Lieuallen et al, 2001).…”

Effect of curcumin on the nitric oxide induced structural and functional modifications of high molecular mass goat brain cystatin

“…Из-за своей важной функции они включаются в различные патофизиологические процессы, включая болезнь Альцгеймера [16], церебральную амилоидную ангиопатию [17] и другие нейродегенеративные заболевания [25].…”